Caudal (Cdx) transcription factors have been implicated in the development of trunk and tail structures across all major animal groups by controlling the generation, sequential addition and identity of posterior body segments. We have shown that knock down of Cdx function in a vertebrate embryo additionally causes a non- segmented region of the nervous system, namely the spinal cord, to become segmented and to form ectopic hindbrain rhombomeres in the trunk. In reciprocal gain-of-function experiments we have shown that Cdx- overexpression is sufficient to cause a segmented structure, namely the hindbrain, to lose aspects of its segmental character and take on features of the spinal cord. We propose that the function of Cdx factors in the vertebrate nervous system may be to prevent the development of segments analogous to hindbrain rhombomeres, thus allowing the formation of an unsegmented spinal cord. We additionally propose that Cdx factors normally function to limit the size of the hindbrain and spinal cord territories, allowing for the proper patterning of the Central Nervous System. In this proposal we will place the Cdx genes within a working context of what is already known about hindbrain development in which an extensive literature already exists. In addition we hope to determine the important cellular and genetic interactions involving Cdx function within the spinal cord and to show that these interactions may be conserved within vertebrates to allow for the specification of the posterior neural tube. In this proposal, we use a variety of molecular, genetic and embryological techniques to address this previously unsuspected role of Cdx factors within the nervous system. Public Health Relevance: Structural birth defects have been shown to increase the rates of such disorders as autism and mental retardation in surviving patients. Neural tube defects often develop within the first few weeks of pregnancy. Anencephaly, spina bifida and other neural tube defects are known to have both genetic and environmentally- induced components of susceptibility.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM067714-06
Application #
7595039
Study Section
Development - 1 Study Section (DEV1)
Program Officer
Haynes, Susan R
Project Start
2002-07-01
Project End
2012-02-28
Budget Start
2009-03-01
Budget End
2010-02-28
Support Year
6
Fiscal Year
2009
Total Cost
$318,036
Indirect Cost
Name
University of Chicago
Department
Biology
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Chang, Jessie; Skromne, Isaac; Ho, Robert K (2016) CDX4 and retinoic acid interact to position the hindbrain-spinal cord transition. Dev Biol 410:178-189
Warga, Rachel M; Mueller, Rachel L; Ho, Robert K et al. (2013) Zebrafish Tbx16 regulates intermediate mesoderm cell fate by attenuating Fgf activity. Dev Biol 383:75-89
Mueller, Rachel Lockridge; Huang, Cheng; Ho, Robert K (2010) Spatio-temporal regulation of Wnt and retinoic acid signaling by tbx16/spadetail during zebrafish mesoderm differentiation. BMC Genomics 11:492
Warga, Rachel M; Kane, Donald A; Ho, Robert K (2009) Fate mapping embryonic blood in zebrafish: multi- and unipotential lineages are segregated at gastrulation. Dev Cell 16:744-55
Ahn, Daegwon; Ho, Robert K (2008) Tri-phasic expression of posterior Hox genes during development of pectoral fins in zebrafish: implications for the evolution of vertebrate paired appendages. Dev Biol 322:220-33
Skromne, Isaac; Thorsen, Dean; Hale, Melina et al. (2007) Repression of the hindbrain developmental program by Cdx factors is required for the specification of the vertebrate spinal cord. Development 134:2147-58
Hurley, Imogen A; Mueller, Rachel Lockridge; Dunn, Katherine A et al. (2007) A new time-scale for ray-finned fish evolution. Proc Biol Sci 274:489-98