We are interested in the morphogenesis of the vertebrate axis and more particularly in the patterning and differentiation of the metameric structures of the body. In the vertebrate embryo, the most overt metameric structures are the somites, which give rise to the segmented structures of the body including the axial skeleton, the dermis of the back and all skeletal muscles. The central theme of the research relevant to this application is to understand the cascade of events, which regulate the segmentation of the body plan of vertebrate embryos at the molecular level. We will essentially focus on the study of a molecular oscillator called the """""""" Segmentation Clock"""""""" which we identified a few years ago. This molecular clock whose rhythm parallels that of segmentation was originally discovered in the chick embryo as pulses of mRNA coding for specific genes in the presomitic mesoderm (PSM). The Segmentation Clock has now been identified in fish, chick and mouse and controls the periodic expression of """"""""Cyclic Genes """""""" which are, so far, all related to the Notch pathway. Neither the mechanism underlying the Segmentation Clock nor its precise role in the segmentation process are currently understood. A major question to be asked regarding the molecular machinery of the Segmentation Clock concerns the role of Notch signaling. Our preliminary studies and genetic evidence in mouse and fish suggest that this pathway plays an important role in the control of the oscillations but it is not known whether it acts in the core mechanism of the oscillator. A major aim of this project will be to carry out experiments at the molecular and cellular level to characterize the role of the Notch pathway in the function of the oscillator. We also showed that FGF signaling controls the activation of the segmentation program and the positioning of somitic boundaries in the chick embryo. We intend to establish the implication of the various components of the FGF pathway in this process, and we will examine the interaction of FGF signaling with the Segmentation Clock. Finally, we have provided evidence for a coupling between the Segmentation Clock and the activation or maintenance of Hox genes during axis formation, and we intend to further characterize this interaction during chick embryogenesis. The understanding of the functioning of the Segmentation Clock is of considerable clinical relevance, since in humans mutations in the genes associated with the function of this oscillator such as delta-like 3 (dll3) result in abnormal segmentation of the vertebral column similar to that seen in the spondylocostal dysostosis syndrome.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD043158-04
Application #
7015099
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Javois, Lorette Claire
Project Start
2003-03-01
Project End
2007-03-31
Budget Start
2006-03-01
Budget End
2007-03-31
Support Year
4
Fiscal Year
2006
Total Cost
$279,474
Indirect Cost
Name
Stowers Institute for Medical Research
Department
Type
DUNS #
614653652
City
Kansas City
State
MO
Country
United States
Zip Code
64110
Chal, Jérome; Guillot, Charlène; Pourquié, Olivier (2017) PAPC couples the segmentation clock to somite morphogenesis by regulating N-cadherin-dependent adhesion. Development 144:664-676
Denans, Nicolas; Iimura, Tadahiro; Pourquié, Olivier (2015) Hox genes control vertebrate body elongation by collinear Wnt repression. Elife 4:
Pourquie, Olivier (2011) Vertebrate segmentation: from cyclic gene networks to scoliosis. Cell 145:650-63
Krol, Aurelie J; Roellig, Daniela; Dequeant, Mary-Lee et al. (2011) Evolutionary plasticity of segmentation clock networks. Development 138:2783-92
Bénazéraf, Bertrand; Francois, Paul; Baker, Ruth E et al. (2010) A random cell motility gradient downstream of FGF controls elongation of an amniote embryo. Nature 466:248-52
Zhang, Shaobing O; Mathur, Sachin; Hattem, Gaye et al. (2010) Sex-dimorphic gene expression and ineffective dosage compensation of Z-linked genes in gastrulating chicken embryos. BMC Genomics 11:13
Wright, David; Ferjentsik, Zoltan; Chong, Shang-Wei et al. (2009) Cyclic Nrarp mRNA expression is regulated by the somitic oscillator but Nrarp protein levels do not oscillate. Dev Dyn 238:3043-3055
Iimura, Tadahiro; Denans, Nicolas; Pourquie, Olivier (2009) Establishment of Hox vertebral identities in the embryonic spine precursors. Curr Top Dev Biol 88:201-34
Gomez, Céline; Pourquié, Olivier (2009) Developmental control of segment numbers in vertebrates. J Exp Zool B Mol Dev Evol 312:533-44
Iimura, Tadahiro; Pourquie, Olivier (2008) Manipulation and electroporation of the avian segmental plate and somites in vitro. Methods Cell Biol 87:257-70

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