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Genetic and Epigenetic Regulations of SHH-GLI Target Genes by TCF/LEF Proteins in the Developing CNS

by
Hui Wang
B.S. Life Science College, Nankai University Tianjin, China - 2001



Thesis Advisor: Michael P. Matise, Ph.D.
Graduate Program in Molecular Genetics,
Microbiology & Immunology


CABM, Room 010
Piscataway

Wednesday, December 15, 2010
2:00 p.m.


Abstract

Orderly generation of the vertebrate central nervous system (CNS) requires the proper spatio-temporal generation of progenitor cells during neurogenesis. In the ventral ventricular zone, the graded secreted Shh signal regulates specific sets of transcription factors within responding cells that implement cell type genetic growth and differentiation programs. While it is only now becoming understood that Shh, signaling through the Gli transcription factors, is necessary to establish five distinct ventral progenitor domains (p0, p1, p2, pMN, and p3) that give rise to unique classes of neurons and glia, it remains unclear whether other pathways or factors modulate or collaborate with the Shh-Gli signaling in ventral spinal cord development.

Currently, the Tcf/Lef protein family (HMG-box transcription factors) is extensively studied in the canonical Wnt signaling pathway. Tcf3 and Tcf7L2/Tcf4 are expressed in specific patterns in the ventral neural tube during development. In my thesis work, I have discovered that Tcf3/4 proteins are required for proper ventral patterning, and function by differentially regulating two Shh-Gli target genes, Nkx2.2 and Olig2. Both genetic experiments and functional in vivo studies show that Tcf repressor activity is necessary to establish the p3 domain-restricted expression of Nkx2.2, and serves to elevate both the strength and duration of Shh-Gli signaling necessary for its induction, but not Olig2. Together, these findings suggest that Tcf repressor activity plays an important role in setting threshold levels necessary to activate gene expression by graded Shh signaling in the ventral CNS.

In addition, I found evidence that the repressive actions of Tcf factors on Nkx2.2 involve histone deacetylase (HDAC) activity via physical association with Groucho/TLE “bridge” proteins. These data demonstrate that a Shh-Gli signaling independent transcriptional response involves an epigenetic transcriptional mechanism which shapes the precise spatio-temporal reaction to Shh-Gli signaling during lineage segregation in the developing neural tube.


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