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Krumlauf Lab
Robb Krumlauf, Ph.D.
Scientific Director
rek@stowers.org

Regulatory pathways patterning the vertebrate brain and body plan in development, disease and evolution

     Our laboratory is interested in understanding the molecular and cellular pathways that govern patterning of the nervous system and body plan of vertebrate embryos during development; how they are altered or affected in human diseases; and how these pathways are conserved in evolution. One biological focus of the group is the hindbrain and its relationship to head development. This is a good model system for addressing fundamental patterning problems in neurobiology related to cell signaling, proliferation, migration, commitment, identity and differentiation. The hindbrain is a complex co-ordination center in the vertebrate CNS and an important source of patterning information that influences the generation of head and facial structures. It serves as a higher order relay center that controls respiration, blood pressure, arousal and wakefulness and it contains the nuclei and fibers of the cranial nerves, which innervate the muscles of the head and neck, transmit sensory information on hearing, balance and taste and control the cardiovascular and gastrointestinal systems.

     The formation of regional diversity in the hindbrain is achieved through a process of segmentation, whereby neural tissue is transiently divided into seven segmental units, termed rhombomeres. Each rhombomere defines a lineage-restricted cellular compartment that creates a distinct microenvironment. This allows each segment to adopt a unique set of molecular and cellular properties distinct from its immediate neighbors, and ultimately give rise to well-defined regions of the adult brain. This segmental organization is critical for patterning of the cranial neural crest and establishing tissue interactions essential for proper head development. Our long-term goal is to understand the coordinated mechanisms that control the process of segmentation.

     A molecular focus of our interest in development has centered on the Hox homeobox gene network. We have demonstrated that there is extended homology between the vertebrate and Drosophila Hox/HOM homeotic complexes and that these transcription factors have a conserved role in the molecular mechanisms that specify regional identity and morphogenesis in many embryonic tissues. Based on highly ordered and segment-restricted patterns of gene expression and loss and gain-of-function analyses in several vertebrate systems, we have demonstrated that Hox genes play multiple roles in diverse aspects of segmentation. Using evolutionary comparisons between the Hox complexes of different species, combined with experimental embryology and transgenic analyses, we have begun to build a picture of the tissue interactions, signals and transcriptional regulatory components upstream of the Hox cascade that modulate their expression and function. Furthermore, by characterizing cofactors (MEIS and PBX) that work with HOX proteins to regulate their DNA binding properties, we have facilitated our ability to identify downstream target sites and genes in the Hox cascade. By developing techniques that allow genetic marking, lineage tracing, and tissue transplantation in cultured embryos we are able to simultaneously analyze changes in gene expression and cell behaviors in the developing head of wild type and mutant mouse embryos. This provides new insight into plasticity of cellular patterning and tissue interactions required to control head morphogenesis. We have devised embryonic assays to screen for the signals involved in this process and those that influence anterior-posterior patterning in the CNS. Through this process we have isolated novel factors that modulate the Wnt and other known signaling pathways.

     We are interested in studying how the Hox genetic pathways that control brain development are related to the roles of these genes in patterning other tissues, such as the skeleton, limbs, digestive systems and organs. Hox genes are not only important for normal development, but they appear to be critical targets associated with human diseases. Knowledge of the genes and pathways that control Hox expression and brain patterning provides candidates for investigating diseases and genetic syndromes in the nervous systems and other tissues. Abnormal Hox expression occurs in many cancers and leukemias and some of the genetic lesions arise in factors that may contribute to regulation of Hox pathways. A future direction of our research will be to investigate the direct and indirect roles of Hox genes in disease to provide insight into ways of developing strategies for prevention, diagnosis and treatment of genetic diseases.

     To approach our research problems we exploit the basic conservation of patterning processes by using a variety of experimental model systems (mouse, chick, frog, fish and fly) each with their own advantages. Furthermore, we are developing methods for in vivo gene transfer, cell grafting and embryo culture and combining them with techniques in embryology, molecular biology, imaging, genetics, cell biology genomics and bioinformatics.

Academic Appointments: Professor, Department of Anatomy & Cell Biology, The University of Kansas School of Medicine; Professor, The University of Kansas Neurosciences Graduate Program; Professor, Department of Oral Biology, The University of Missouri at Kansas City Dental School

Selected publications

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, Wu M, Gogol M, Alexander T, Seidel CW, Wiedemann LM, Krumlauf R, Shilatifard A. Global analysis of H3K4 methylation defines MLL (KMT2A) as a gene-specific activator of transcription [published ahead of print August 24 2009]. Mol Cell. 2009. Abstract

Alexander T, Nolte C, Krumlauf R. Hox Genes and Segmentation of the Hindbrain and Axial Skeleton. Annu Rev Cell Dev Biol. 2009;25:431-456. Abstract

Parrish M, Nolte C, Krumlauf R. Hox genes expression. In: L Squire, ed. New Encyclopedia of Neuroscience. 4th ed: Academic Press; 2009:1221-1231.

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

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

Tümpel S, Cambronero F, Sims C, Krumlauf R, Wiedemann LM. Gene Networks in Development and Evolution Special Feature Sackler Colloquium: 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;Epub Open Access:14-41.

Ellies DL, Viviano B, McCarthy J, Rey JP, Itasaki N, Saunders S, Krumlauf R. Bone Density Ligand, Sclerostin, Directly Interacts With LRP5 but Not LRP5(G171V) to Modulate Wnt Activity. J Bone Miner Res. 2006;21:1738-1749. Abstract

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

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.

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.

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

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.

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).

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.

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.

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.

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.

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.

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.

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.

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

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

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

Manzanares M, Wada H, Itasaki N, Trainor P, Krumlauf R, Holland PWH. Conservation and elaboration of Hox gene regulation during evolution of the vertebrate head. Nature. 2000;408:854-857. 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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Itasaki N, Sharpe J, Morrison A, Krumlauf R. Reprogramming Hox expression in the vertebrate hindbrain: influence of paraxial mesoderm and rhombomere transposition. Neuron. 1996;16:487-500. Abstract.

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