Robb Krumlauf, Ph.D.

816.926.4051

Member

1992
European Molecular Biology Organisation

1999
Academy of Medical Sciences, UK

2003
American Academy of Arts and Sciences

2007
Fellow, American Association for the Advancement of Science

2016
National Academy of Sciences

Awards

1975 NIH Pre-Doctoral Fellow

1979 NATO/NSF Postdoctoral Fellow

1982 NIH Postdoctoral Fellow

2018 Edwin G. Conklin Medal, Society for Developmental Biology

Education

B.E., chemical engineering
Vanderbilt University

Ph.D., developmental biology
Ohio State University

Krumlauf Lab

Robb Krumlauf, Ph.D.

Investigator; Scientific Director Emeritus

Professor, Department of Anatomy & Cell Biology
The University of Kansas School of Medicine

Professor, Neurosciences Graduate Program
University of Kansas

Professor, Department of Oral Biology
University of Missouri at Kansas City Dental School

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Profile

If you think there are people-oriented careers, and then there is science, you haven’t met Robb Krumlauf. Whether he is recounting his pioneering studies of genes regulating the vertebrate body plan or envisioning Stowers’ role in the future of biomedical research, one word dominates Krumlauf’s conversation—collegiality.

Mice with HoxB Bacterial Artificial Chromosomes containing multiplex fluorescent protein reporters (top) allow the visualization of Hox expression in mouse hindbrain segments via multispectral imaging. Image: Dr. Robb Krumlauf

“I enjoy the process of discovery,” says Krumlauf, who is Investigator and Scientific Director Emeritus at Stowers. “That satisfaction is personal at some level, but I really enjoy sharing success in a group as much as individually.”

In the molecular revolution he has been on the forefront of two fields—mouse genetics and developmental biology—which is remarkable, because Krumlauf, who earned a B.E. in chemical engineering from Vanderbilt University in 1970, never took an upper division biology class until he held his first job as Chief Chemical Engineer at Stokely Van Camp. His work involved the creation of drug delivery systems, requiring him to learn biology in continuing education classes.

Five years into the job he left to devote himself to earning a Ph.D. (1979) in Developmental Biology at Ohio State University and by the mid-80’s had completed two postdocs, one at Beatson Institute for Cancer Research in Glasgow, Scotland, and a second at Fox Chase Institute for Cancer Research in Philadelphia, where he studied with mouse geneticist Shirley Tilghman.

Few mentors influenced Krumlauf as profoundly as Tilghman, president emerita of Princeton. In her lab, Krumlauf did research on what were then emerging techniques of inserting genes into the mouse germline, a breakthrough in creation of “transgenic” mice useful to answer fundamental biological questions. But what he recalls vividly are Tilghman’s people skills.

“We worked 24/7 like demons in Shirley’s lab but she made it fun because she cared about us as people,” says Krumlauf, observing that occasionally investigators overlook less “accomplished” members of a lab. “Shirley knew that not everybody will run a lab but made people aware of their strengths and helped them find career options. People left her lab feeling good about themselves.”

Although tempted by offers from Institutions needing a mouse geneticist, for his first faculty job Krumlauf opted to immerse himself in embryology at one of that field’s epicenters, England’s National Institute of Medical Research (NIMR) in the Mill Hill region of London.

There, between 1985 and 2000 he conducted research on expression and function of DNA-binding proteins encoded by Hox genes in a part of the brainstem called the hindbrain, which controls automatic functions like breathing or blood pressure. Krumlauf’s group showed that expression of Hox genes along anterior to posterior regions or “segments” of the hindbrain not only dictated that region’s function but remarkably corresponded to the sequential alignment of Hox genes clustered along a particular mouse chromosome, a phenomenon initially observed in fruit flies. These studies were among the first to show that genes defining position along the body axis were conserved structurally and functionally in the genomes of vertebrates and insects.

Krumlauf attributes his Mill Hill productivity in part to his colleagues—including department heads Brigid Hogan and Peter Rigby, and junior faculty Andy McMahon, Robin Lovell-Badge, David Wilkinson, Jim Smith, and Rosa Beddington, among others—a who’s who of preeminent embryologists and developmental biologists.“For developmental biologists, it was like the heyday of atomic physics,” says Krumlauf. “Suddenly you realized how the universe works!”

Initially, Krumlauf had planned to stay only briefly in the UK, but the mix of competitiveness and collegiality kept him at Mill Hill for 16 years. During his last decade there he served as Head of the Division of Developmental Neurobiology. When he first heard about the kind of biomedical science envisioned at the then embryonic Stowers Institute in the late 90’s, he was at first uninterested, but soon reconsidered. “I felt like there was a real need for a model like the Max Planck, Pasteur or Mill Hill—American style,” says Krumlauf, who became the first senior faculty member to set up shop when the institute opened in 2000.

Krumlauf’s work here has mirrored ideas that have come full circle since his career began. The discoveries of developmental biologists in the 80’s and 90’s were primarily of commonality. “Back then, I didn’t believe that genes that Drosophila geneticists were discovering would have common roles in mice,” says Krumlauf. “But soon we went from thinking that all organisms are different to surprise at discovering unifying principles. Now we are returning to a search for the origin of all the diversity.”

The mammalian hindbrain is divided into segments (left panel). Corresponding segmental patterns of Hox expression (right panel) can be detected using multispectral imaging and fluorescent protein reporter mice. Image: Dr. Robb Krumlauf

In that pursuit, Krumlauf has at Stowers made evolutionary comparisons of how Hox genes are regulated across species as diverse as mice, chicks and fish to understand both similarities and differences in mechanisms that switch on specific Hox genes and control their function in a species-specific manner.

He is also excited about understanding how different species deploy their highly similar molecular toolkits to form diverse structures, such as unique facial features. This interest has resulted in recent studies of a factor called Wise that regulates patterns of vertebrate tooth, bone and mammary development. He finds it rewarding that his studies on Wise have also opened new possibilities for treating human bone density disorders, such as osteoporosis.

In what he calls his “volunteer time,” Krumlauf serves as Editor and Editor-In-Chief of the journal Developmental Biology, is on the Editorial Board of many peer-reviewed journals and serves on review panels for many external funding organizations, including the NIH, Howard Hughes Medical Institute and The Wellcome Trust.

Research Summary

The goal of our research is to understand Hox transcriptional regulatory networks that control patterning of the mammalian brain, skeleton, and basic body plan during development, disease, and evolution.

Molecular studies and genomic analyses have revealed that a wide range of animals have a surprisingly similar collection of genes in their genomes. The basis for generating and patterning different tissues within an animal and diversity between species therefore largely depends upon mechanisms that control how and when these genes are utilized. For this reason, it is important to understand the “wiring blueprint” or regulatory networks which control the dynamic patterns of gene expression and cell signaling necessary to form tissues and organs in development. This also facilitates approaches for exploring how such gene regulatory networks may vary in contributing to diversity during evolution. Knowledge of these interactive regulatory networks is also relevant to human health because alterations in their activities can be associated with clinical abnormalities and disease.

The molecular focus of our group is centered on the Hox homeotic genes, which encode highly conserved homeodomain transcription factors that play similar regulatory roles in both vertebrates and invertebrates. Genetic and regulatory analyses in many model systems have demonstrated that the Hox family of transcription factors provides a coordinated and highly conserved molecular framework (code) for specifying and patterning distinct regional properties of tissues during development, tissue homeostasis, and adult life. Mutations that alter Hox genes or their regulation can lead to leukemia, metastatic tumorigenesis, and a variety of patterning defects of the brain, craniofacial region, limb, and skeleton. Therefore, our laboratory is interested in understanding the underlying mechanisms of how Hox-dependent transcriptional regulatory networks control the formation and patterning of the basic mammalian body plan during development, how they are associated with or affected in diseases, and the roles of these pathways in generating morphological diversity during vertebrate evolution.

The major biological focus of our research is aimed at understanding hindbrain, craniofacial, and skeletal development. The hindbrain is a complex coordination center for motor activity, breathing rhythms, and many unconscious functions, and is highly conserved in vertebrates. The hindbrain also plays a key role in regulating the formation of head structures, such as bone and connective tissue, via the generation of cranial neural crest cells. The paraxial mesoderm generates somites, which give rise to diverse bones of the axial skeleton. Segmentation plays an important role in the functional organization of these tissues. The cellular processes of segmentation in both the hindbrain and somite systems depend upon establishing ordered patterns of Hox gene expression as a mechanism for generating a combinatorial code that specifies unique identities to the segments and their derivatives (Alexander et al 2009).

Our long-term goal is to understand the regulatory basis of tissue patterning and morphogenesis by generating a deep mechanistic level of knowledge of the Hox-dependent regulatory cascades which underlie their diverse functional roles in development, disease, and evolution. Towards this end, we investigate the upstream regulatory mechanisms which generate ordered and restricted patterns of Hoxexpression and characterize downstream Hox target genes necessary for elaborating their function. From a biochemical standpoint we want to determine the nature of their in vivo binding sites and rules for target site recognition, how they are recruited to these loci as Hox protein complexes, and the basis for specificity of individual Hox proteins. This insight will aid knowledge of how Hox proteins elaborate their functional roles in specifying unique properties to tissues through the control of cell and developmental processes. To address these questions, we use mouse embryos and ES cells as a primary model system in combination with diverse genetic, genomic, biochemical, and imaging approaches. We also exploit the extensive conservation in hindbrain and somite segmentation between vertebrates by utilizing a variety of other model systems (human cells, chick, zebrafish, and lamprey) to investigate similarities and differences in patterning processes during vertebrate evolution. More information about research model organisms and some of the emerging model systems that my lab and other Stowers researchers study to understand biological processes and relevance to diseases can be found in this Stowers Report article.

Project Summaries:

A. Mechanisms regulating activation and expression of Hox genes
In mammals, there are 39 Hox genes organized into four complexes (HoxA, HoxB, HoxC, HoxD) each located on a different chromosome. These clusters arose through duplication and divergence from a common ancestral cluster. An intriguing property of Hox genes is that their linear arrangement within each complex mirrors their sequential activation and function in the embryo. This phenomenon is known as colinearity and it serves to establish the nested combinations of Hox proteins along the A-P axis that form a combinatorial code for specifying unique regional identities in different tissues. Opposing retinoid and Wnt/Fgf signaling centers drive axial growth and extension and the Hox clusters integrate cues from these signaling pathways to pattern growing tissues. Hence, understanding how regulation of Hox genes is coupled to axial growth and segmentation through these signaling pathways is important for building a picture of the fundamental mechanisms that govern elaboration of the basic body plan.

1. Enhancer sharing and long range regulation of Hox genes and lincRNAs
A number of retinoic acid response elements (RAREs) that modulate transcriptional activity through bounding of heterodimeric RAR:RXR nuclear hormone receptors have been identified within the mammalian Hox clusters. Our analyses have revealed that these RAREs can function as cis-regulatory elements to modulate expression of multiple HoxB genes in a cluster through enhancer sharing and long-range regulation (Nolte et al 2013, Ahn et al 2014). Targeted mutagenesis and gene editing data (CRISPR/cas9) of the endogenous cluster reveals that these RAREs play an important functional role in long-range regulation of multiple HoxB genes during embryogenesis and tissue homeostasis. Some of the RAREs embedded within the Hox clusters are also involved in regulating long intergenic non-coding RNAs (lincRNAs) and microRNAs present in the HoxB cluster (DeKumar et al 2015 DeKumar and Krumlauf 2016). This data provides evidence for shared regulation of coding and non-coding transcripts that may contribute to conservation of clustered Hox organization in animals. The positions of several of these RAREs appear to be highly conserved in Hox clusters during chordate evolution suggesting they may be components of the ancient mechanism which sets up nested domains of axial Hox expression.

Ongoing projects are aimed at investigating the regulatory mechanisms and functional roles of RAREs and lincRNAs in developmental, disease and evolutionary processes. We utilize CRISPR/Cas9 to generate mutations in single and multiple RAREs and lincRNAs in the endogenous mouse Hox clusters to probe in vivo function and synergy between elements. Recombineering of bacterial artificial chromosomes (BAC) containing the mouse HoxB or HoxA clusters and gene editing are also being used to label multiple Hox genes with different fluorescent protein reporters (Parrish et al 2014). Multispectral imaging of hindbrain tissue from these transgenic or gene edited mice is then performed to simultaneously monitor the expression of multiple Hox genes over time in lines with wild type or mutated RAREs (Ahn et al 2014). The mice carrying diverse fluorescent reporters also provide a means for isolating and identifying distinct groups of cells based on their combinations of Hox expression which is useful for global expression profiling and genomic analyses. These studies are uncovering novel roles for retinoids, lincRNAs and Hox genes in neural, cardiac, and hematopoietic development and enhance understanding of how embryos establish appropriate programs of gene expression in response to RA, Wnt and Fgf signaling.

2. Chromatin state, topological domains and boundaries
Genes flanking the four Hox clusters have very different expression properties in comparison to Hox genes implying distinct modes of regulation. Since cis-regulatory elements that modulate Hox expression can work over long range we wish to understand how their activity restricted to the Hox genes and do not impact neighboring genes (Nolte et al 2013). Current models suggest that this may be mediated by chromatin looping, boundary, and/or insulator elements. In an ongoing project, through a combination of regulatory analyses, phylogenetic footprinting, and biochemical approaches we identified a novel sequence flanking the HoxB complex. Functional studies indicate this element functions as a boundary or insulator to generate a HoxB regulatory domain or landscape distinct from the neighboring genes. Deletion of this region from the endogenous cluster alters regulation of adjacent genes. Similar conserved elements are positioned adjacent to other Hox clusters. We are currently performing a series of experiments to characterize the properties, components, and mechanisms through which this boundary region establishes a chromosomal domain to facilitate control of HoxB expression and whether similar mechanisms are used by other Hox clusters.

Dynamic patterns of gene expression can depend upon changes in the state or modification of chromatin. We have utilized the programmed differentiation of mouse ES cells into neural fates and dissected tissue from mouse embryos in combination with genomic technologies to investigate links between chromatin state and regulation of Hox genes (Lin et al 2011, DeKumar et al 2015). Epigenetic changes in chromatin modification and the binding of regulatory proteins to Hox clusters reveal dynamic and specific changes in epigenetic marks associated with activated and/or repressed states and transcriptional activity of Hox genes. Transcriptional profiling using RNA from the differentiating ES cells and mouse tissues has uncovered an extensive array of non-coding RNAs from both strands of the four Hox clusters. While some of these correspond to known miRs or regulatory RNAs, many are novel and display dynamic changes over time (DeKumar et al 2015, DeKumar and Krumlauf 2016). Several of the novel non-coding RNAs map to cis-regions which correlate with changes in chromatin state identified in genomic assays or in regulatory modules. Current projects are testing whether these non-coding RNAs directly participate in the activation or regulation of Hox genes or other developmental targets.

3. Cis-regulatory elements controlling segmentation
Sequence comparisons between vertebrate Hox clusters in combination with transgenic regulatory analyses have provided insight into mechanisms governing Hox expression in hindbrain segments (rhombomeres). A series of cis-regulatory modules underlie the generation of discrete domains of segmental expression in the hindbrain. Expression of any given Hox gene is the result of the combined activity of a series of cis-modules that control specific subsets of the segmental expression pattern and each cis-module is subject to its own regulatory inputs and timing. We have used this information to construct a gene regulatory network for vertebrate hindbrain segmentation (Alexander et al 2009, Tümpel et al 2009, Krumlauf 2016, Parker et al 2016). Current projects apply proteomic and biochemical approaches to expand our knowledge of the upstream transcription factors, cofactors, and signaling pathways that activate Hox expression through these hindbrain cis-regulatory modules. Experiments are also being conducted to investigate the basis for cis-regulation of Hox genes in somites and cranial neural crest cells.

4. Evolution of mechanisms coupling Hox expression to hindbrain segmentation
The hindbrain gene regulatory network we have characterized in jawed vertebrates controls patterning by integrating segmentation with the generation of segmentally-restricted domains of Hox gene expression. We are investigating when this network evolved and when Hox genes became coupled to it. Non-vertebrate chordates display nested domains of axial Hox gene expression but lack hindbrain segmentation and segmental regulatory elements (Manzanares et al 2000, Natale et al 2011). The sea lamprey, a jawless fish, is poised to provide unique insights into vertebrate origins due to its phylogenetic position at the base of the vertebrate tree. We have cloned lamprey Hox genes and investigated their relationship to the hindbrain regulatory network (Smith et al 2013). In collaboration with Marianne Bronner at Caltech, using a novel tool that allows cross-species comparisons of regulatory elements between jawed and jawless vertebrates we have demonstrated that lamprey Hox genes are coupled to hindbrain segmentation in a manner conserved with jawed vertebrates (Parker et al 2014, Parker et al 2016). This work has shown that coupling of Hox gene expression to segmentation of the hindbrain is a defining feature and an ancient trait with an origin at the base of vertebrate evolution. We are expanding this analysis and investigating how it extends to Hox regulation in cranial neural crest networks.

B. Hox targets, binding sites, and cofactors

1. Transcriptional profiling segmental expression in the hindbrain
We are characterizing rhombomere-specific patterns of gene expression which are important in generating individual segments and identifying genes which are dependent upon Hox activity. Towards this end we have performed transcriptional profiling on whole dissected hindbrains and individual hindbrain segments isolated by laser capture microscopy from transgenic lines expressing fluorescent protein reporters in specific segments. This readily enables the identification and isolation of segments in the absence of overt morphological segmentation. Transcriptional profiling by microarrays and RNA-seq on tissue and segments isolated from wild type and Hox mutant embryos help to identify genes dependent upon Hox activity. Projects in this area are uncovering a number of pathways and targets genes downstream of Hox involved in regulating neurogenesis in the hindbrain.

2. Genome-wide identification Hox binding sites
Very little is known about the downstream target loci Hox proteins regulate and how they are recruited to these loci as Hox protein complexes. One challenge is that all 39 mammalian Hox proteins are highly similar. Hence, their individual specificity is likely to be modulated by differences in cofactors, interacting proteins, target binding sites, or other unknown processes. A major current focus involves projects identifying in vivo relevant Hox response elements on a genome-wide basis to gain insight into how Hox proteins potentiate their functional roles. We are using transgenic mice, gene editing, and the programmed differentiation of ES cells carrying epitope-tagged versions of different Hox proteins in combination with ChIP-seq genomic technologies to identify in vivo binding regions for Hox proteins and their associated target genes. In addition to the known co-factors, such as Pbx and Meis, this analysis is revealing that in vivo binding sites for Hox proteins display a range of novel sequence motifs. The emerging data indicates that different Hox proteins can bind to distinct target regions and is providing insight into new potential partners and cofactors for Hox activity. Current projects are aimed at validating the role of these Hox binding sites in regulatory assays and comparing them to genes whose expression is altered in transcriptional profiling analyses. This approach is serving to identify direct down-stream regulatory targets and pathways under control of individual Hox proteins and to illuminate common targets for multiple Hox proteins. In light of the conserved nature and function of Hox proteins, in collaboration with Julia Zeitlinger’s lab at the Stowers Institute, we are also conducting genome-wide analyses of Hox targets in Drosophila. The goal is to compare and contrast Hox targets in mammalian cells and Drosophila to look for shared properties and common target pathways.

3. Proteomic approaches to identification of Hox cofactors and complexes
Hox proteins bind DNA and exert their regulatory activity in part through interactions with cofactors and recruitment of coactivator/corepressor complexes. To begin to identify some of these interacting proteins, we are collaborating with Michael Washburn and Laurence Florens of the Proteomics Center at the Stowers Institute to use MudPIT-based mass spectroscopy approaches. Exploiting ES cells, gene edited mice and transgenic mice carrying epitope-tagged versions of different Hox proteins in combination with immune precipitation of the tagged Hox proteins followed by protein sequencing we are searching for interacting partners. To complement this approach, in collaboration with Ron and Joan Conaway, we are using Hox binding sites identified by genomic approaches as high affinity templates in combination with nuclear extracts to assemble binding complexes and characterize them by protein sequencing.

Selected Publications

Marangoni P, Charles C, Ahn Y, Seidel K, Jheon A, Ganss B, Krumlauf R, Viriot L, Klein OD. Down-regulation of FGF signaling by Spry4 over-expression leads to shape impairment, enamel irregularities, and delayed signaling center formation in the mouse molar. [published ahead of print May 23 2019]. JBMR Plus.2019. Abstract

Nolte C, De Kumar B, Krumlauf R. Hox genes: Downstream "effectors" of retinoic acid signaling in vertebrate embryogenesis. [published ahead of print May 22 2019]. Genesis.2019:e23306. Abstract

Parker HJ, Bronner ME, Krumlauf R. An atlas of anterior hox gene expression in the embryonic sea lamprey head: Hox-code evolution in vertebrates. Dev Biol.2019. Abstract | Original Data

Parker HJ, De Kumar B, Green SA, Prummel KD, Hess C, Kaufman CK, Mosimann C, Wiedemann LM, Bronner ME, Krumlauf R. A Hox-TALE regulatory circuit for neural crest patterning is conserved across vertebrates. Nat Commun.2019;10:1189. doi: 1110.1038/s41467-41019-09197-41468. Abstract | Original Data

Krumlauf R. Hox genes, clusters and collinearity. Int J Dev Biol.2018;62:659-663. Abstract

Kim J, Ahn Y, Adasooriya D, Woo EJ, Kim HJ, Hu KS, Krumlauf R, Cho SW. Shh Plays an Inhibitory Role in Cusp Patterning by Regulation of Sostdc1. J Dent Res.2019;98:98-106. Abstract | Original Data

Qian P, De Kumar B, He XC, Nolte C, Gogol M, Ahn Y, Chen S, Li Z, Xu H, Perry JM, Hu D, Tao F, Zhao M, Han Y, Hall K, Peak A, Paulson A, Zhao C, Venkatraman A, Box A, Perera A, Haug JS, Parmely T, Li H, Krumlauf R, Li L. Retinoid-Sensitive Epigenetic Regulation of the Hoxb Cluster Maintains Normal Hematopoiesis and Inhibits Leukemogenesis. Cell Stem Cell.2018;22:740-754 e747. Abstract | Original Data

Parker HJ, Pushel I, Krumlauf R. Coupling the roles of Hox genes to regulatory networks patterning cranial neural crest. Dev Biol.2018;444 Suppl 1:S67-S78. Abstract

Smith JJ, Timoshevskaya N, Ye C, Holt C, Keinath MC, Parker HJ, Cook ME, Hess JE, Narum SR, Lamanna F, Kaessmann H, Timoshevskiy VA, Waterbury CKM, Saraceno C, Wiedemann LM, Robb SMC, Baker C, Eichler EE, Hockman D, Sauka-Spengler T, Yandell M, Krumlauf R, Elgar G, Amemiya CT. The sea lamprey germline genome provides insights into programmed genome rearrangement and vertebrate evolution. Nat Genet.2018;50:270-277. Abstract | Original Data

De Kumar B, Parker HJ, Paulson A, Parrish ME, Zeitlinger J, Krumlauf R. Hoxa1 targets signaling pathways during neural differentiation of ES cells and mouse embryogenesis. Dev Biol.2017;432:151-164. Abstract | Original Data

Parker HJ, Krumlauf R. Segmental arithmetic: summing up the Hox gene regulatory network for hindbrain development in chordates [published ahead of print August 3 2017]. Wiley Interdiscip Rev Dev Biol.2017. Abstract

Li C, Lan Y, Krumlauf R, Jiang R. Modulating Wnt Signaling Rescues Palate Morphogenesis in Pax9 Mutant Mice. J Dent Res.2017;96:1273-1281. Abstract

Kousa YA, Roushangar R, Patel N, Walter A, Marangoni P, Krumlauf R, Klein OD, Schutte BC. IRF6 and SPRY4 Signaling Interact in Periderm Development. J Dent Res.2017;96:1306-1313. Abstract

Ahn Y, Sims C, Murray MJ, Kuhlmann PK, Fuentes-Antras J, Weatherbee SD, Krumlauf R. Multiple modes of Lrp4 function in modulation of Wnt/beta-catenin signaling during tooth development. Development.2017;144:2824-2836. Abstract | Original Data

De Kumar B, Parker HJ, Parrish ME, Lange JJ, Slaughter BD, Unruh JR, Paulson A, Krumlauf R. Dynamic regulation of Nanog and stem cell-signaling pathways by Hoxa1 during early neuro-ectodermal differentiation of ES cells. Proc Natl Acad Sci U S A.2017;114:5838-5845. Abstract | Original Data

De Kumar B, Parker HJ, Paulson A, Parrish ME, Pushel I, Singh NP, Zhang Y, Slaughter BD, Unruh JR, Florens L, Zeitlinger J, Krumlauf R. HOXA1 and TALE proteins display cross-regulatory interactions and form a combinatorial binding code on HOXA1 targets. Genome Res.2017;27:1501-1512. Abstract | Original Data

Prochazkova M, Hakkinen TJ, Prochazka J, Spoutil F, Jheon AH, Ahn Y, Krumlauf R, Jernvall J, Klein OD. FGF signaling refines Wnt gradients to regulate patterning of taste papillae. Development.2017;144:2212-2221. Abstract

Parker HJ, Bronner ME, Krumlauf R. The vertebrate Hox gene regulatory network for hindbrain segmentation: Evolution and diversification: Coupling of a Hox gene regulatory network to hindbrain segmentation is an ancient trait originating at the base of vertebrates. BioEssays.2016;38:526-538. Abstract | Original Data

Krumlauf R. Hox Genes and the Hindbrain: A Study in Segments. Curr Top Dev Biol.2016;116:581-596.

McEllin JA, Alexander TB, Tumpel S, Wiedemann LM, Krumlauf R. Analyses of fugu hoxa2 genes provide evidence for subfunctionalization of neural crest cell and rhombomere cis-regulatory modules during vertebrate evolution. Dev Biol.2016;409:530-542. Abstract | Original Data

De Kumar B, Krumlauf R. HOXs and lincRNAs: Two sides of the same coin. Sci Adv.2015;2:e1501402. Abstract

De Kumar B, Parrish ME, Slaughter BD, Unruh JR, Gogol M, Seidel C, Paulson A, Li H, Gaudenz K, Peak A, McDowell W, Fleharty B, Ahn Y, Lin C, Smith E, Shilatifard A, Krumlauf R. Analysis of dynamic changes in retinoid-induced transcription and epigenetic profiles of murine Hox clusters in ES cells. Genome Res.2015;25:1229-1243. Abstract | Original Data

Lara-Castillo N, Kim-Weroha NA, Kamel MA, Javaheri B, Ellies DL, Krumlauf R, E, Thiagarajan G, Johnson ML. In vivo mechanical loading rapidly activates beta-catenin signaling in osteocytes through a prostaglandin mediated mechanism. Bone.2015;76:58-66. Abstract

Parker HJ, Bronner ME, Krumlauf R. A Hox regulatory network of hindbrain segmentation is conserved to the base of vertebrates. Nature.2014;514:490-493. Abstract | Original Data

Parrish M, Ahn Y, Nolte C, De Kumar B, Krumlauf R. Hox Complex Analysis Through BAC Recombineering. Methods Mol Biol.2014;1196:59-87. Abstract | Original Data

Ellies DL, Economou A, Viviano B, Rey JP, Paine-Saunders S, Krumlauf R, Saunders S. Wise Regulates Bone Deposition through Genetic Interactions with Lrp5. PLoS One.2014;9:e96257. Abstract | Original Data

Ahn Y, Mullan HE, Krumlauf R. Long-range regulation by shared retinoic acid response elements modulates dynamic expression of posterior Hoxb genes in CNS development. Dev Biol.2014;388:134-144.Abstract | Original Data

Nolte C, Jinks T, Wang X, Martinez Pastor MT, Krumlauf R. Shadow enhancers flanking the HoxB cluster direct dynamic Hox expression in early heart and endoderm development. Dev Biol.2013;383:158-173. Abstract | Original Data

Vieux-Rochas M, Mascrez B, Krumlauf R, Duboule D. Combined function of HoxA and HoxB clusters in neural crest cells. Dev Biol.2013;382:293-301. Abstract

Soshnikova N, Dewaele R, Janvier P, Krumlauf R, Duboule D. Duplications of hox gene clusters and the emergence of vertebrates. Dev Biol.2013;378:194-199. Abstract

Smith JJ, Kuraku S, Holt C, Sauka-Spengler T, Jiang N, Campbell MS, Yandell MD, Manousaki T, Meyer A, Bloom OE, Morgan JR, Buxbaum JD, Sachidanandam R, Sims C, Garruss AS, Cook M, Krumlauf R, Wiedemann LM, Sower SA, Decatur WA, Hall JA, Amemiya CT, Saha NR, Buckley KM, Rast JP, Das S, Hirano M, McCurley N, Guo P, Rohner N, Tabin CJ, Piccinelli P, Elgar G, Ruffier M, Aken BL, Searle SM, Muffato M, Pignatelli M, Herrero J, Jones M, Brown CT, Chung-Davidson YW, Nanlohy KG, Libants SV, Yeh CY, McCauley DW, Langeland JA, Pancer Z, Fritzsch B, de Jong PJ, Zhu B, Fulton LL, Theising B, Flicek P, Bronner ME, Warren WC, Clifton SW, Wilson RK, Li W. Sequencing of the sea lamprey (Petromyzon marinus) genome provides insights into vertebrate evolution. Nat Genet.2013;45:415-421. Abstract | Original Data

Ahn Y, Sims C, Logue JM, Weatherbee SD, Krumlauf R. Lrp4 and Wise interplay controls the formation and patterning of mammary and other skin appendage placodes by modulating Wnt signaling. Development.2013;140:583-593. Abstract | Original Data

Gaertner B, Johnston J, Chen K, Wallaschek N, Paulson A, Garruss AS, Gaudenz K, De Kumar B, Krumlauf R, Zeitlinger J. Poised RNA Polymerase II Changes over Developmental Time and Prepares Genes for Future Expression. Cell Rep.2012;2:1670-1683. Abstract | Original Data

Natale A, Sims C, Chiusano ML, Amoroso A, D'Aniello E, Fucci L, Krumlauf R, Branno M, Locascio A. Evolution of anterior Hox regulatory elements among chordates. BMC Evol Biol.2011;11:330. Abstract

Charles C, Hovorakova M, Ahn Y, Lyons D, Marangoni P, Churava S, Biehs B, Jheon A, Lesot H, Balooch G, Krumlauf R, Viriot L, Peterkova R, Klein O. Regulation of tooth number by fine-tuning levels of receptor-tyrosine kinase signaling. Development.2011; 138:4063-4071. Abstract

Lin C, Garrett A, De Kumar B, Smith E, Gogol M, Seidel C, Krumlauf R, Shilatifard A. Dynamic Transcriptional Events in Embryonic Stem Cells Mediated by the Super Elongation Complex, Genes Dev 2011:25:1486-1498. Abstract

Parrish M, Unruh J, Krumlauf R. BAC modification through serial or simultaneous use of CRE/Lox technology. J Biomed Biotechnol.2011;2011:924068. Abstract

Ahn Y, Sanderson B, Klein O, Krumlauf R. Inhibition of Wnt signaling by Wise/Sostdc1 and negative feedback from Shh controls tooth number and patterning. Development 2010:137:3221-3231. Abstract

Alexander T, Nolte C, Krumlauf R. Hox genes and segmentation of the hindbrain and axial skeleton. Ann Rev Cell Dev Biol.2009;25:431-456. Abstract

Tümpel S, Wiedemann LM, Krumlauf R. Hox genes and segmentation of the vertebrate hindbrain. Curr Top Dev Biol. 2009/08/05 ed; 2009;88:103-137. Abstract

Wang P, Lin C, Smith ER, Guo H, Sanderson BW, Wu M, Gogol M, Alexander T, Seidel C, Wiedemann LM, Ge K, Krumlauf R, Shilatifard A. Global analysis of H3K4 methylation defines MLL family member targets and points to a role for MLL1-mediated H3K4 methylation in the regulation of transcriptional initiation by RNA polymerase II. Mol Cell Biol.2009;29:6074-6085. Abstract

Bogni S, Trainor P, Natarajan D, Krumlauf R, Pachnis V. Non-cell-autonomous effects of Ret deletion in early enteric neurogenesis. Development.2008;135:3007-3011. Abstract

Inoue T, Inoue YU, Asami J, Izumi H, Nakamura S, Krumlauf R. Analysis of mouse Cdh6 gene regulation by transgenesis of modified bacterial artificial chromosomes. Dev Biol.2008;315:506-520. Abstract

Tümpel S, Cambronero F, Sims C, Krumlauf R, Wiedemann LM. A regulatory module embedded in the coding region of Hoxa2 controls expression in rhombomere 2. Proc Natl Acad Sci U S A.2008;105:20077-20082. Abstract

Rinon A, Lazar S, Marshall H, Buchmann-Moller S, Neufeld A, Elhanany-Tamir H, Taketo MM, Sommer L, Krumlauf R, Tzahor E. Cranial neural crest cells regulate head muscle patterning and differentiation during vertebrate embryogenesis. Development.2007;134:3065-3075. Abstract

Tümpel S, Cambronero F, Ferretti E, Blasi F, Wiedemann LM, Krumlauf R. Expression of Hoxa2 in rhombomere 4 is regulated by a conserved cross-regulatory mechanism dependent upon Hoxb1. Dev Biol.2007;302:646-660. Abstract

Nolte C, Krumlauf R. Expression of Hox Genes in the Nervous System of Vertebrates. In: S Papageorgiou, ed. Hox Gene Expression. Austin, TX: Landes Bioscience & Springer; 2006:4-41.

Ellies DL, Krumlauf R. Bone formation: the nuclear matrix reloaded. Cell.2006;125:840-842. Abstract

Ellies DL, Viviano B, McCarthy J, Rey JP, Itasaki N, Saunders S, Krumlauf R. Bone density ligand, Sclerostin, directly interacts with LRP5 but not LRP5G171V to modulate Wnt activity. J Bone Miner Res.2006;21:1738-1749. Abstract

Tümpel S, Cambronero F, Wiedemann LM, Krumlauf R. Evolution of cis elements in the differential expression of two Hoxa2 coparalogous genes in pufferfish (Takifugu rubripes). Proc Natl Acad Sci U S A.2006;103:5419-5424. Abstract

Ferretti E, Cambronero F, Tümpel S, Longobardi E, Wiedemann LM, Blasi F, Krumlauf R. Hoxb1 Enhancer and Control of Rhombomere 4 Expression: Complex Interplay between PREP1-PBX1-HOXB1 Binding Sites. Mol Cell Biol.2005;25:8541-8552. Abstract

Rosa-Molinar E, Krumlauf R, Pritz MB. Hindbrain development and evolution: past, present, and future. Brain Behav Evol.2005;66:219-221. Abstract

Serpente P, Tümpel S, Ghyselinck NB, Niederreither K, Wiedemann LM, Dolle P, Chambon P, Krumlauf R, Gould AP. Direct crossregulation between retinoic acid receptor {beta} and Hox genes during hindbrain segmentation. Development.2005;132:503-513. Abstract

Kusumi K, Mimoto MS, Covello KL, Beddington RS, Krumlauf R, Dunwoodie SL. Dll3 pudgy mutation differentially disrupts dynamic expression of somite genes. Genesis.2004;39:115-121. Abstract

Trainor PA, Bronner-Fraser M, Krumlauf R. Neural Crest Cells. In: RP Lanza, ed. Book Chapter for 2 vol. work, The Handbook of Stem Cells. Boston, MA: Elsevier Academic; 2004;1:219-232.

Mercurio S, Latinkic B, Itasaki N, Krumlauf R, Smith JC. Connective-tissue growth factor modulates WNT signalling and interacts with the WNT receptor complex. Development.2004;131:2137-2147. Abstract

Powles N, Marshall H, Economou A, Chiang C, Murakami A, Dickson C, Krumlauf R, Maconochie MK. Regulatory analysis of the mouse Fgf3 gene: Control of embryonic expression patterns and dependence upon sonic hedgehog (Shh) signalling. Dev Dyn.2004;230:44-56. Abstract

Gavalas A, Ruhrberg C, Livet J, Henderson CE, Krumlauf R. Neuronal defects in the hindbrain of Hoxa1, Hoxb1 and Hoxb2 mutants reflect regulatory interactions among these Hox genes. Development.2003;130:5663-5679. Abstract

Itasaki N, Jones CM, Mercurio S, Rowe A, Domingos PM, Smith JC, Krumlauf R. Wise, a context-dependent activator and inhibitor of Wnt signalling. Development. 2003;130:4295-4305. Abstract.

Ivins S, Pemberton K, Guidez F, Howell L, Krumlauf R, Zelent A. Regulation of Hoxb2 by APL-associated PLZF protein. Oncogene.2003;22:3685-3697. Abstract

Pattyn A, Vallstedt A, Dias JM, Samad OA, Krumlauf R, Rijli FM, Brunet JF, Ericson J. Coordinated temporal and spatial control of motor neuron and serotonergic neuron generation from a common pool of CNS progenitors. Genes Dev. 2003;17:729-737. Abstract.

Bel-Vialar S, Itasaki N, Krumlauf R. Initiating Hox gene expression: in the early chick neural tube differential sensitivity to FGF and RA signaling subdivides the HoxB genes in two distinct groups. Development. 2002;129:5103-5115. Abstract.

Krumlauf R. Spring forward and fall back: dynamics in formation of somite boundaries. Dev Cell. 2002;3:605-606. Abstract.

Manzanares M, Nardelli J, Gilardi-Hebenstreit P, Marshall H, Martinez-Pastor M, Krumlauf R, Charnay P. Krox20 and kreisler cooperate in the transcriptional control of segmental expression of Hoxb3 in the developing hindbrain. EMBO J. 2002;21:365-376. Abstract.

Theil T, Ariza-McNaughton L, Manzanares M, Brodie J, Krumlauf R, Wilkinson DG. Requirement for down-regulation of kreisler during late patterning of the hindbrain. Development. 2002;129:1477-1485. Abstract.

Trainor P, Krumlauf R. Riding the crest of Wnt signaling. Science. 2002;297:781-783.

Trainor P, Ariza-McNaughton L, Krumlauf R. Role of the isthmus and FGFs in resolving the paradox of neural crest plasticity and prepatterning. Science. 2002;295:1288-1291. Comments about this paper may be found in Nature Reviews Neuroscience 2002;3:254 and Nature 2002;416:493-494. To link to the Nature commentary, you must register with their site (free account).

Trainor P, Sobieszczuk D, Wilkinson D, Krumlauf R. Signalling between the hindbrain and paraxial tissues dictates neural crest migration pathways. Development. 2002;129:433-442. Abstract.

Tümpel S, Maconochie M, Wiedemann LM, Krumlauf R. Conservation and diversity in the cis-regulatory networks that integrate information controlling expression of Hoxa2 in hindbrain and cranial neural crest cells in vertebrates. Dev Biol. 2002;246:45-56. Abstract.

Domingos PM, Itasaki N, Jones CM, Mercurio S, Sargent MG, Smith JC, Krumlauf R. The Wnt/ß-catenin pathway posteriorizes neural tissue in Xenopus by an indirect mechanism dependent upon FGF signalling. Dev Biol. 2001;239:148-160. Abstract.

Gavalas A, Trainor P, Ariza-McNaughton L, Krumlauf R. Synergy between Hoxa1 and Hoxb1: The relationship between arch patterning and the generation of cranial neural crest. Development. 2001;128:3017-3027. Abstract.

Manzanares M, Bel-Vialar S, Ariza-McNaughton L, Ferretti E, Marshall H, Maconochie M, Blasi F, Krumlauf R. Independent regulation of initiation and maintenance phases of Hoxa3 expression in the vertebrate hindbrain involve auto and cross-regulatory mechanisms. Development. 2001;128:3595-3607. Abstract.

Di Rocco G, Gavalas A, Pöpperl H, Krumlauf R, Mavilio F, Zappavigna V. The recruitment of SOX/OCT complexes and the differential activity of HOXA1 and HOXB1 modulate the Hoxb1 auto-regulatory enhancer function. J Biol Chem. 2001;276:20506-20515. Abstract.

Inoue T, Krumlauf R. An impulse to the brain-- using in vivo electroporation. Nature Neurosci Suppl. 2001;4:6-8. Abstract.

Kwan C-T, Tsang S-L Krumlauf R, Sham M-H. Regulatory analysis of the mouse Hoxb3 gene: Multiple elements work in concert to direct temporal and spatial patterns of expression. Dev Biol. 2001;232:176-190. Abstract.

Maconochie M, Nonchev S, Manzanares M, Marshall H, Krumlauf R. Differences in Krox20-dependent regulation of Hoxa2 and Hoxb2 during hindbrain development. Dev Biol. 2001;233:468-481. Abstract.

Trainor P, Krumlauf R. Hox genes, neural crest cells and branchial arch patterning. Current Opinion in Cell Biology. 2001;13:698-705. Abstract.

Bulman MP, Kusumi K, Frayling TM, McKeown C, Garrett C, Lander ES, Krumlauf R, Hattersley AT, Ellard S, Turnpenny PD. Mutations in the human Delta homologue, DLL3, cause axial skeletal defects in spondylocostal dysostosis. Nature Genet. 2000;24:438-441. Abstract.

Ferretti E, Marshall H, Pöpperl H, Maconochie M, Krumlauf R, Blasi F. Segmental expression of Hoxb2 in r4 requires two separate sites that integrate cooperative interactions between Prep1, Pbx and Hox proteins. Development. 2000;127:155-166. Abstract.

Golding JP, Trainor P, Krumlauf R, Gassmann M. Defects in pathfinding by cranial neural crest cells in mice lacking the neuregulin receptor ErbB4. Nature Cell Biol. 2000;2:103-109. Abstract.

Kmita M, van der Hoeven F, Zákány J, Krumlauf R, Duboule D. Mechanisms of Hox gene colinearity: transposition of the anterior Hoxb1 gene into the posterior HoxD complex. Genes Dev. 2000;14:198-211. Abstract.

Manzanares M, Cordes S, Ariza-McNaughton L, Sadl V, Maruthainar K, Barsh G, Krumlauf R. Conserved and distinct roles of kreisler in regulation of the paralogous Hoxa3 and Hoxb3 genes. Development. 1999;126:759-769. Abstract.

Trainor P, Krumlauf R. Plasticity in mouse neural crest cells reveals a novel patterning role for cranial mesoderm. Nature Cell Biol. 2000;2:96-102. Abstract.

Trainor P, Krumlauf R. Patterning the cranial neural crest: Hindbrain segmentation and Hox gene plasticity. Nature Rev Neurosci. 2001;1:116-124. Abstract.

Davenne M, Maconochie M, Neun R, Pattyn A, Chambon P, Krumlauf R, Rijli FM. Hoxa2 and Hoxb2 control dorsoventral patterns of neuronal development in the rostral hindbrain. Neuron 1999;22:677-691. Abstract.

Itasaki N, Bel-Vialar S, Krumlauf R. "Shocking" developments in chick embryology: electroporation and in ovo gene expression. Nature Cell Biol. 1999;1:E203-207. Abstract.

Maconochie M, Krishnamurthy R, Nonchev S, Meier P, Manzanares M, Mitchell PJ, Krumlauf R. Regulation of Hoxa2 in cranial neural crest cells involves members of the AP-2 family. Development. 1999;126:1483-1494. Abstract.

Manzanares M, Cordes S, Ariza-McNaughton L, Sadl V, Maruthainar K, Barsh G, Krumlauf R. Conserved and distinct roles of kreisler in regulation of the paralogous Hoxa3 and Hoxb3 genes. Development.1999;126:759-769. Abstract.

Manzanares M, Trainor P, Nonchev S, Ariza-McNaughton L, Brodie J, Gould A, Marshall H, Morrison A, Kwan C-T, Sham M, Wilkinson DG, Krumlauf R. The role of kreisler in segmentation during hindbrain development. Dev Biol. 1999;211:220-237. Abstract.

Sharpe J, Lettice L, Hecksher-Sørensen J, Fox M, Hill Robb Krumlauf R. Identification of Sonic hedgehog as a candidate gene responsible for the polydactylous mouse mutant Sasquatch. Cur Biol. 1999;9:97-100. Abstract.

Gould A, Itasaki N, Krumlauf R. Initiation of rhombomeric Hoxb4 expression requires induction by somites and a retinoic pathway. Neuron. 1998;21:39-51. Abstract.

Sharpe J, Nonchev S, Gould A, Whiting J, Krumlauf R. Selectivity, sharing and competitive interactions in the regulation of Hoxb genes. EMBO J. 1998;17:1788-1798. Abstract.

Studer M, Gavalas A, Marshall H, Ariza-McNaughton L, Rijli F, Chambon P, Krumlauf R. Genetic interactions between Hoxa1 and Hoxb1 reveal new roles in regulation of early hindbrain patterning. Development. 1998;125:1025-1036. Abstract.

Aparicio S, Hawker K, Cottage A, Mikawa Y, Zuo L, Venkatesh B, Chen E, Krumlauf R, Brenner S. Organization of the Fugu rubripes Hox clusters, evidence for continuing evolution of vertebrate Hox complexes. Nature Genet. 1997;16:79-84. Abstract.

Gould A, Morrison A, Sproat G, White R, Krumlauf R. Positive cross-regulation and enhancer sharing: two mechanisms for specifying overlapping Hox expression patterns. Genes Dev. 1997;11:900-913. Abstract.

Maconochie M, Nonchev S, Studer M, Chan S-K, Pöpperl H, Sham M-H, Mann R, Krumlauf R. Cross-regulation in the mouse HoxB complex: the expression of Hoxb-2 in rhombomere 4 is regulated by Hoxb-1. Genes Dev. 1997;11:1885-1895. Abstract.

Manzanares M, Cordes S, Kwan C-T, Sham M-H, Barsh G, Krumlauf R. Segmental regulation of Hoxb-3 by kreisler. Nature. 1997;387:191-195. Abstract.

Lumsden A, Krumlauf R. Patterning the vertebrate neuraxis. Science.1996;274:1109-1115. Abstract

Studer M, Lumsden A, Ariza-McNaughton L, Bradley A, Krumlauf R. Altered segmental identity and abnormal migration of motor neurons in mice lacking Hoxb-1. Nature. 1996;384:630-634. Abstract.

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