Distinct Functional and Temporal Requirements for Zebrafish Hdac1 during Neural Crest-Derived Craniofacial and Peripheral Neuron Development

Abstract

The regulation of gene expression is accomplished by both genetic and epigenetic means and is required for the precise control of the development of the neural crest. In hdac1b382 mutants, craniofacial cartilage development is defective in two distinct ways. First, fewer hoxb3a, dlx2 and dlx3-expressing posterior branchial arch precursors are specified and many of those that are consequently undergo apoptosis. Second, in contrast, normal numbers of progenitors are present in the anterior mandibular and hyoid arches, but chondrocyte precursors fail to terminally differentiate. In the peripheral nervous system, there is a disruption of enteric, DRG and sympathetic neuron differentiation in hdac1b382 mutants compared to wildtype embryos. Specifically, enteric and DRG-precursors differentiate into neurons in the anterior gut and trunk respectively, while enteric and DRG neurons are rarely present in the posterior gut and tail. Sympathetic neuron precursors are specified in hdac1b382 mutants and they undergo generic neuronal differentiation but fail to undergo noradrenergic differentiation. Using the HDAC inhibitor TSA, we isolated enzyme activity and temporal requirements for HDAC function that reproduce hdac1b382 defects in craniofacial and sympathetic neuron development. Our study reveals distinct functional and temporal requirements for zebrafish hdac1 during neural crest-derived craniofacial and peripheral neuron development.

Using zebrafish in systems toxicology for developmental toxicity testing

“…VPA and topiramate have been shown to cause a hypomorphic lower jaw (Yamashita et al 2014;Inoue et al 2015). Many anti-epileptic drugs can also inhibit histone deacetylase (HDAC) (Eyal et al 2004); the protein HDAC1 regulates neural crest-derived craniofacial development (Ignatius et al 2013). These findings suggest that prenatal exposure to anti-epileptic drugs may cause neural crest-derived craniofacial malformation through inhibiting HDAC.…”

Epigenetic regulation in neural crest development

“…Thus, during normal melanogenesis, HDAC1 is required to repress FoxD3 expression that in turn de-represses MITFa to allow melanophore specification, migration and differentiation (Ignatius et al, 2008). In addition, HDAC1 is also involved in neural crest derived craniofacial and peripheral neuron development (Ignatius et al, 2013). Craniofacial cartilage defects are observed in mutant HDAC1 zebrafish in which fewer branchial arch precursors marked by hoxb3a, dlx2, and dlx3 are specified and chondrocyte precursors fail to differentiate.…”

“…The differentiation of enteric and dorsal root ganglion neurons in the posterior gut and tail are also disrupted in these mutant embryos. Interestingly, sympathetic neurons precursors can successfully undergo generic neuronal differentiation but fail to become noradrenergic (Ignatius et al, 2013). Overall, HDAC1 is required for distinct developmental processes and its activity is present in a broad range of cell types during neural crest derived differentiation.…”

Epigenetics in ENS development and Hirschsprung disease

“…In zebrafish, hdac1 is required for the development of the eye, CNS and neural crest cell populations Cunliffe, 2004;Nambiar and Henion, 2004;Stadler, 2005;Yamaguchi et al, 2005). Therefore, there seems to be a specific requirement for hdac1 in ENS formation, at least in this animal model (Ignatius et al, 2013). HDCA4 is also highly associated with neural crest related diseases and syndromes (Park et al, 2006;Alsdorf and Wyszynski, 2005).…”