Abstract
BackgroundHistone deacetylase-4 (Hdac4) is a class II histone deacetylase that inhibits the activity of transcription factors. In humans, HDAC4 deficiency is associated with non-syndromic oral clefts and brachydactyly mental retardation syndrome (BDMR) with craniofacial abnormalities.ResultsWe identify hdac4 in zebrafish and characterize its function in craniofacial morphogenesis. The gene is present as a single copy, and the deduced Hdac4 protein sequence shares all known functional domains with human HDAC4. The zebrafish hdac4 transcript is widely present in migratory cranial neural crest (CNC) cells of the embryo, including populations migrating around the eye, which previously have been shown to contribute to the formation of the palatal skeleton of the early larva. Embryos injected with hdac4 morpholinos (MO) have reduced or absent CNC populations that normally migrate medial to the eye. CNC-derived palatal precursor cells do not recover at the post-migratory stage, and subsequently we found that defects in the developing cartilaginous palatal skeleton correlate with reduction or absence of early CNC cells. Palatal skeletal defects prominently include a shortened, clefted, or missing ethmoid plate, and are associated with a shortening of the face of young larvae.ConclusionsOur results demonstrate that Hdac4 is a regulator of CNC-derived palatal skeletal precursors during early embryogenesis. Cleft palate resulting from HDAC4 mutations in human patients may result from defects in a homologous CNC progenitor cell population.
Highlights
Histone deacetylase-4 (Hdac4) is a class II histone deacetylase that inhibits the activity of transcription factors
At 17 hpf, the overlap of expression between hdac4 and pdgfra was more apparent (Figure 1E-G), with expression of both genes dorsal to the eye, medial to the eye, and posterior to the eye. mRNA transcript of hdac4 is broadly expressed throughout the head after 17 hpf, until about 72 hpf, when expression becomes localized to sox9-expressing cartilages in the pharyngeal arches (Figure 1H, J arrows), mesenchyme surrounding the cartilages, and the pectoral fin (Figure 1H)
Defects of the palatal skeletal cartilages in hdac4-MO injected embryos result secondarily from early disruption of migratory or premigratory cranial neural crest (CNC) cells During normal development, the anteriorly-located CNC cells migrate in streams located posterior, medial, and dorsal to the eye, the medial cells eventually accumulating at the optic stalk at 20–24 hpf, before going on to form the medial region of the ethmoid plate, the skeletal region affected most in our hdac4 MO-injected embryos [12,13,14]
Summary
Histone deacetylase-4 (Hdac4) is a class II histone deacetylase that inhibits the activity of transcription factors. HDAC4 deficiency is associated with non-syndromic oral clefts and brachydactyly mental retardation syndrome (BDMR) with craniofacial abnormalities. Disruption of CNC cell behavior, or defects in CNC-derived tissue patterning, as might arise when function of a developmental regulatory. Hdac is a class II histone deacetylase that by binds to other HDACs and myocyte enhancing factor-2 (Mef2) to inhibit transcription factor binding to target DNA [5,6,7,8]. Single-nucleotide polymorphisms (SNPs) in HDAC4 are associated with non-syndromic oral clefts [9], and haploinsufficiency of HDAC4 causes brachydactyly mental retardation syndrome (BDMR) [OMIM: 600430] with associated craniofacial abnormalities [10]. Establishing the function of Hdac in craniofacial development is critical for understanding how disruption of this gene causes craniofacial skeletal defects
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