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.
Highlights
The neural crest is a transient embryonic cell population that gives rise to craniofacial cartilages, neurons and glia of the peripheral nervous system and pigment cells, among other cell types [1]
In hdac1b382 mutants the neurocranium cartilages are stained by alcian blue, the neurocranium itself is reduced in size and the ethmoid plate elements fail to fuse at the midline as it does wildtype embryos [33]
Our results of phenotypic analysis of hdac1b382 mutants and the selective temporal manipulation of histone deacetylases (HDACs) function during development with the HDAC inhibitor trichostatin A (TSA) demonstrate a reiterative requirement for hdac1 function during craniofacial neural crest development, including the specification of neural crest posterior branchial arch progenitors, cranial neural crest cell migration and morphogenesis and, the differentiation of all neural crest-derived craniofacial cartilage elements
Summary
The neural crest is a transient embryonic cell population that gives rise to craniofacial cartilages, neurons and glia of the peripheral nervous system and pigment cells, among other cell types [1]. Multiple regulators of gene expression required for neural crest development have been identified. These include the Bmp, Fgf, Notch and Wnt signaling pathways [2,3,4] and key transcription factors including foxd3 [5,6,7,8], tfap2a [9,10,11], snail1b [12,13], pax3 [14], sox9 [15,16] and sox10 [17,18]. The acetylation status of histones within eukaryotic cells is catalyzed by two types of enzymes known as histone deacetylases (HDACs) and histone acetyltransferases (HATs) [27,28,29]. HDAC enzymes are classified into four classes based on homology studies [30]
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