ZFIN ID: ZDB-PUB-090521-141
Zebrafish Hdac1 is reiteratively and differentially required during neural crest cell development and Hdac1 is a positive regulator of the non canonical Wnt signaling pathway
Ignatius, M.S.
Date: 2008
Source: Ph.D. Thesis : (Thesis)
Registered Authors: Ignatius, Myron
Keywords: none
MeSH Terms: none
PubMed: none
The neural crest is a transient embryonic cell population that contributes to multiple cell types in the vertebrate embryo including chromatophores, craniofacial cartilages, neurons and glia of the peripheral nervous system. Neural crest cell (NCC) development has been used extensively to explore mechanisms of cell fate specification, differentiation and migration, which more broadly illuminate mechanisms in the development of multicellular organisms. Through a combination of forward and reverse genetic approaches using mutants, morpholinos and a chemical inhibitor, I identify in vivo requirements of hdac1 (histone deacetylase1) in NCC development. The zebrafish mutant colgate (col) /hdac1 exhibits defective NCC-derived melanophore, peripheral neuron and craniofacial development. Additionally, hdac1col mutants also display defects in the extension of the body axis and the migration of branchiomotor neurons. I demonstrate that hdac1 is specifically required for melanophore and branchial arch specification. In melanophores, I define a likely mechanism regulating specification. Characterization of the hdac1col mutant craniofacial defects, suggests that hdac1 is also required for proper terminal differentiation and migration of manidubular and hyoid arch cartilages. Similarly, hdac1 is required for the differentiation of PNS-derived dorsal root ganglion (DRG), enteric and sympathetic neurons. Specifically, in sympathetic neurons, hdac1 is required for acquisition of neurotransmitter characteristics. The HDAC inhibitor trichostatinA (TSA) inhibits multiple HDACs including Hdac1. Interestingly, TSA phenocopies multiple aspects of hdac1col development, suggesting that hdac1 is an important HDAC in embryogenesis. Using TSA, I define temporal requirements of HDAC/hdac1 function during craniofacial and sympathetic neuron differentiation. In hdac1col/ tfap2a mutant/ morphant embryos, there are severe reductions in melanophore and craniofacial derivatives at all stages analyzed, when compared to single mutants, suggesting a new additive or synergistic genetic interaction between hdac1 and tfap2a that is required for NCC-derived melanophore and craniofacial development. Finally, activation of the non-canonical Wnt/PCP pathway that is required for axis extension, in hdac1col mutant embryos, rescues axis extension defects. This suggests that hdac1 acts as a positive regulator of the non-canonical Wnt/PCP pathway. Additionally, hdac1 normally regulates the caudal migration of facial hindbrain branchiomotor neurons, independently of the non-canonical Wnt/ PCP pathway.
Ph.D. Thesis, Ohio State University