Abstract
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.
Highlights
Wolf-Hirschhorn Syndrome (WHS) is a developmental disorder characterized by intellectual disability, delayed pre- and postnatal growth, heart and skeletal defects, and seizures (Hirschhorn et al, 1965; Wolf et al, 1965; Zollino et al, 2000; Battaglia et al, 2015)
Given the commanding role of cranial neural crest (CNC) cell proliferation, migration, and differentiation in properly coordinated facial patterning of most of these affected tissues, we hypothesized that certain WHS-affected genes could play critical roles in neural crest maintenance, motility, or specification, and that their depletion would disproportionately impact tissues derived from the neural crest
We performed in situ hybridization with DIG-labeled antisense RNA probes against four genes within and proximal to the last defined WHS critical region (Figure 1 and Supplementary Figure S1; for in situ hybrization controls against mRNA sense strands, see Supplementary Figure S1Y)
Summary
Wolf-Hirschhorn Syndrome (WHS) is a developmental disorder characterized by intellectual disability, delayed pre- and postnatal growth, heart and skeletal defects, and seizures (Hirschhorn et al, 1965; Wolf et al, 1965; Zollino et al, 2000; Battaglia et al, 2015). Craniofacial malformations are one of the most prevalent forms of congenital defects (Gorlin et al, 2001; Trainor, 2010), and can significantly complicate palliative care and quality of life (Merrow, 2016). A striking commonality in the tissues that are impacted by WHS is that a significant number derive from the CNC. Little is known about how the vast diversity of genetic disruptions that underlie WHS pathology can contribute to craniofacial malformation, and no study has sought to characterize impacts of these genotypes explicitly on CNC behavior
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