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Trainor Lab
Paul Trainor, Ph.D.
Associate Investigator
pat@stowers.org
Craniofacial Development
     Understanding the mechanisms that control head and facial development is an important problem, as one-third of all human congenital birth defects exhibit craniofacial abnormalities. Neural crest cells are a migratory cell population born early during embryonic development, which ultimately generates much of the bone, cartilage, connective tissue, and peripheral nervous system of the head and face. Craniofacial abnormalities are therefore largely attributed to defects in the formation, proliferation, migration and differentiation of neural crest cells. Classical models for craniofacial development suggested that the cell fate and genetic identity of the neural crest is programmed prior to its migration from the neural tube.

     Recently, however, we demonstrated that cranial neural crest cells in mouse embryos are plastic and their development can be influenced by the tissues they interact with during migration. Thus, congenital craniofacial malformations can arise either through intrinsic or extrinsic defects in neural crest development. In the lab, we are currently investigating whether intrinsic neural crest cell defects are responsible for Treacher Collins Syndrome craniofacial abnormalities.

     We have also undertaken gene discovery approaches (ENU mutagenesis and microarray) to identify new genes involved in craniofacial development and neurogenesis and we are focusing in particular on the interactions between the cranial mesoderm and neural crest.

Treacher Collins Syndrome
     Treacher Collins Syndrome (OMIM number 154500) is an autosomal dominant craniofacial disorder that occurs as the result of mutations in the TCOF1 gene, which encodes the nucleolar protein Treacle 1. With an incidence of one in 50,000 Treacher Collins Syndrome is characterized by numerous developmental anomalies such as small jaws, cleft palate and middle and external ear defects. The majority of the facial structures affected in Treacher Collins Syndrome are derived either in part or in their entirety from cranial neural crest cells. We are currently investigating the role of Tcof1 in neural crest cell development as a mechanism for understanding the origins of this particular birth defect as well as possible avenues for prevention and repair.

ENU Mutagenesis
     Mutagenesis of mice with the chemical mutagen, ethylnitrosourea (ENU) is an efficient technique for generating and identifying mouse models that mimic specific human disease processes. In the lab we have undertaken a small scale ENU mutagenesis screen aimed at identifying novel genes involved in craniofacial development. We are currently characterizing 10 recessive mutations which exhibit holoprosencephaly, brain and open neural tube defects, cleft palate and hypoplastic branchial arch and limb development. Possible gene candidates have been identified in the retinoid and sonic hedgehog signaling pathways.

Cranial Mesoderm
     The cranial mesoderm predominantly generates the vasculature and musculature in the head but also forms part of bony skull vault and base of the skull. Previously, we demonstrated that the cranial mesoderm can influence neural crest cell migration and patterning. From a microarray screen we have identified a large number of mesoderm specific genes that may play key roles in craniofacial development. In particular we are examining the roles played by members of the Vefg, Igf and Fox gene families in regulating the interactions between cranial mesoderm and neural crest cells.

Academic Appointment: Assistant Professor, Department of Anatomy & Cell Biology, The University of Kansas School of Medicine

Selected publications

Iulianella A, Sharma M, Vanden Heuvel GB, Trainor PA. Cux2 functions downstream of Notch signaling to regulate dorsal interneuron formation in the spinal cord. Development. 2009;136:2329-2334. Abstract

Gibb S, Zagorska A, Melton K, Tenin G, Vacca I, Trainor P, Maroto M, Dale JK. Interfering with Wnt signalling alters the periodicity of the segmentation clock. Dev Biol. 2009;330:21-31. Abstract

Sakai D, Trainor PA. Treacher Collins syndrome: Unmasking the role of Tcof1/treacle. Int J Biochem Cell Biol. 2009;41:1229-1232. Abstract

Trainor PA, Dixon J, Dixon MJ. Treacher Collins syndrome: etiology, pathogenesis and prevention. Eur J Hum Genet. 2009;17:275-283. 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

Jones NC, Lynn ML, Gaudenz K, Sakai D, Aoto K, Rey JP, Glynn EF, Ellington L, Du C, Dixon J, Dixon MJ, Trainor PA. Prevention of the neurocristopathy Treacher Collins syndrome through inhibition of p53 function. Nat Med. 2008;14:125-133.  Abstract  Comments about the paper may be found in Nat Med. 2008 Feb;14(2):115-6. Abstract

Iulianella A, Sharma M, Durnin M, Vanden Heuvel GB, Trainor PA. Cux2 (Cutl2) integrates neural progenitor development with cell-cycle progression during spinal cord neurogenesis. Development. 2008;135:729-741.  Abstract

Sandell LL, Sanderson BW, Moiseyev G, Johnson T, Mushegian A, Young K, Rey JP, Ma JX, Staehling-Hampton K, Trainor PA. RDH10 is essential for synthesis of embryonic retinoic acid and is required for limb, craniofacial, and organ development. Genes Dev. 2007;21:1113-1124. Abstract

Crane JF, Trainor PA. Neural Crest Stem and Progenitor Cells. Annu Rev Cell Dev Biol. 2006;22:267-286. Abstract

Dixon J, Jones NC, Sandell LL, Jayasinghe SM, Crane J, Rey JP, Dixon MJ, Trainor PA. Tcof1/Treacle is required for neural crest cell formation and proliferation deficiencies that cause craniofacial abnormalities. Proc Natl Acad Sci U S A. 2006;103:13403-13408. Abstract

Dale JK, Malapert P, Chal J, Vilhais-Neto G, Maroto M, Johnson T, Jayasinghe S, Trainor P, Herrmann B, Pourquie O. Oscillations of the snail genes in the presomitic mesoderm coordinate segmental patterning and morphogenesis in vertebrate somitogenesis. Dev Cell. 2006;10:355-366. Abstract

Noden DM, Trainor PA. Relations and interactions between cranial mesoderm and neural crest populations. J Anat. 2005;207:575-601. Abstract

Kulesa P, Ellies DL, Trainor PA. Comparative analysis of neural crest cell death, migration, and function during vertebrate embryogenesis. Dev Dyn. 2004;229:14-29. Abstract

Iulianella A, Melton KR, Trainor PA. Somitogenesis: breaking new boundaries. Neuron. 2003;40:11-14. Abstract

Iulianella A, Vanden Heuvel G, Trainor PA. Dynamic expression of murine Cux2 in craniofacial, limb, urogenital and neuronal primordia. Gene Expr Patterns. 2003;3:571-577. Abstract

Trainor, PA.  Development. The bills of qucks and duails. Science. 2003;299:523-524. 

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

Trainor PA, 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 3:254 and Nature 416: 493-494. To link to the Nature commentary, you must register with their site (free account).

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

Gavalas A, Trainor PA, Ariza-McNaughton L, Krumlauf R. Synergy between Hoxa1 and Hoxb1: The relationship between arch patterning and the generation of cranial neural crest. Development. 2001;125:3017-3027. Abstract.

Trainor PA, Krumlauf R.  Patterning cranial neural crest: roles for hindbrain segmentation and plasticity of Hox gene expression. Nature Rev Neurosci.  2000;1:116-124. Abstract.

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

Manzanares M, Trainor PA*, Ariza-McNaughton L, Nonchev S, Krumlauf R. Dorsal patterning defects in the hindbrain, roof plate and skeleton in the dreher (dr(J)) mouse mutant. Mech Dev. 2000;94:147-156. Abstract

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

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


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