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Front Physiol 2019 Jan 01;10:431. doi: 10.3389/fphys.2019.00431.
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Wolf-Hirschhorn Syndrome-Associated Genes Are Enriched in Motile Neural Crest Cells and Affect Craniofacial Development in Xenopus laevis.

Mills A , Bearce E , Cella R , Kim SW , Selig M , Lee S , Lowery LA .

Wolf-Hirschhorn Syndrome (WHS) is a human developmental disorder arising from a hemizygous perturbation, typically a microdeletion, on the short arm of chromosome four. In addition to pronounced intellectual disability, seizures, and delayed growth, WHS presents with a characteristic facial dysmorphism and varying prevalence of microcephaly, micrognathia, cartilage malformation in the ear and nose, and facial asymmetries. These affected craniofacial tissues all derive from a shared embryonic precursor, the cranial neural crest (CNC), inviting the hypothesis that one or more WHS-affected genes may be critical regulators of neural crest development or migration. To explore this, we characterized expression of multiple genes within or immediately proximal to defined WHS critical regions, across the span of craniofacial development in the vertebrate model system Xenopus laevis. This subset of genes, whsc1, whsc2, letm1, and tacc3, are diverse in their currently-elucidated cellular functions; yet we find that their expression demonstrates shared tissue-specific enrichment within the anterior neural tube, migratory neural crest, and later craniofacial structures. We examine the ramifications of this by characterizing craniofacial development and neural crest migration following individual gene depletion. We observe that several WHS-associated genes significantly impact facial patterning, cartilage formation, neural crest motility in vivo and in vitro, and can separately contribute to forebrain scaling. Thus, we have determined that numerous genes within and surrounding the defined WHS critical regions potently impact craniofacial patterning, suggesting their role in WHS presentation may stem from essential functions during neural crest-derived tissue formation.

PubMed ID: 31031646
PMC ID: PMC6474402
Article link: Front Physiol
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: fn1 letm1 nelfa nsd2 tacc3 twist1
GO keywords: neural crest cell migration [+]
Morpholinos: letm1 MO1 nelfa MO1 nsd2 MO1 tacc3 MO2

Disease Ontology terms: Wolf-Hirschhorn syndrome [+]
Phenotypes: Xla Wt + letm1 MO (Fig. 3D, FGHI) [+]

Article Images: [+] show captions
References [+] :
Adelman, Promoter-proximal pausing of RNA polymerase II: emerging roles in metazoans. 2012, Pubmed