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Involvement of the zebrafish trrap gene in craniofacial development.

ABSTRACT: Trrap (transformation/transcription domain-associated protein) is a component shared by several histone acetyltransferase (HAT) complexes and participates in transcriptional regulation and DNA repair; however, the developmental functions of Trrap in vertebrates are not fully understood. Recently, it has been reported that human patients with genetic mutations in the TRRAP gene show various symptoms, including facial dysmorphisms, microcephaly and global developmental delay. To investigate the physiological functions of Trrap, we established trrap gene-knockout zebrafish and examined loss-of-function phenotypes in the mutants. The trrap zebrafish mutants exhibited smaller eyes and heads than the wild-type zebrafish. The size of the ventral pharyngeal arches was reduced and the mineralization of teeth was impaired in the trrap mutants. Whole-mount in situ hybridization analysis revealed that dlx3 expression was narrowly restricted in the developing ventral pharyngeal arches, while dlx2b expression was diminished in the trrap mutants. These results suggest that trrap zebrafish mutants are useful model organisms for a human disorder associated with genetic mutations in the human TRRAP gene.

SUBMITTER: Suzuki T

PROVIDER: S-EPMC8692476 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Involvement of the zebrafish trrap gene in craniofacial development.

Suzuki Taichi T Hirai Yo Y Uehara Tomoko T Ohga Rie R Kosaki Kenjiro K Kawahara Atsuo A

Scientific reports 20211221 1

Trrap (transformation/transcription domain-associated protein) is a component shared by several histone acetyltransferase (HAT) complexes and participates in transcriptional regulation and DNA repair; however, the developmental functions of Trrap in vertebrates are not fully understood. Recently, it has been reported that human patients with genetic mutations in the TRRAP gene show various symptoms, including facial dysmorphisms, microcephaly and global developmental delay. To investigate the ph ...[more]

PMID: 34934055

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Project description:Holoprosencephaly (HPE), the most common malformation of the human forebrain, is associated with defects of the craniofacial skeleton. ZIC2, a zinc-finger transcription factor, is strongly linked to HPE and to a characteristic set of dysmorphic facial features in humans. We have previously identified important functions for zebrafish Zic2 in the developing forebrain. Here, we demonstrate that ZIC2 orthologs zic2a and zic2b also regulate the forming zebrafish craniofacial skeleton, including the jaw and neurocranial cartilages, and use the zebrafish to study Zic2-regulated processes that may contribute to the complex etiology of HPE. Using temporally controlled Zic2a overexpression, we show that the developing craniofacial cartilages are sensitive to Zic2 elevation prior to 24hpf. This window of sensitivity overlaps the critical expansion and migration of the neural crest (NC) cells, which migrate from the developing neural tube to populate vertebrate craniofacial structures. We demonstrate that zic2b influences the induction of NC at the neural plate border, while both zic2a and zic2b regulate NC migratory onset and strongly contribute to chromatophore development. Both Zic2 depletion and early ectopic Zic2 expression cause moderate, incompletely penetrant mispatterning of the NC-derived jaw precursors at 24hpf, yet by 2dpf these changes in Zic2 expression result in profoundly mispatterned chondrogenic condensations. We attribute this discrepancy to an additional role for Zic2a and Zic2b in patterning the forebrain primordium, an important signaling source during craniofacial development. This hypothesis is supported by evidence that transplanted Zic2-deficient cells can contribute to craniofacial cartilages in a wild-type background. Collectively, these data suggest that zebrafish Zic2 plays a dual role during craniofacial development, contributing to two disparate aspects of craniofacial morphogenesis: (1) neural crest induction and migration, and (2) early patterning of tissues adjacent to craniofacial chondrogenic condensations.

Dataset Information

Involvement of the zebrafish trrap gene in craniofacial development.

Publications

Involvement of the zebrafish trrap gene in craniofacial development.

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