Ciliary protein Kif7 regulates Gli and Ezh2 for initiating the neuronal differentiation of enteric neural crest cells during development.
basic_science · Level V
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- Record sourced from PubMed, PMID 34644112.
- Also identified by DOI 10.1126/sciadv.abf7472 and PMC identifier 8514102.
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Abstract
Gastrointestinal motility disorders occur frequently in patients with ciliopathy, but the underlying genetic link is unclear. The ciliary protein Kif7 can positively or negatively regulate Hedgehog signaling in different cellular contexts. Mice with neural crest cell (NCC)–specific <i>Kif7</i> deficiency show a marked reduction of enteric NOS<sup>+</sup> inhibitory neurons. Malformation of enteric nervous system (ENS) causes growth retardation and gut motility defect in mice. Mechanistically, <i>Kif7</i> inhibits Gli2 in enteric NCCs (ENCCs), where Gli2 positively regulates the expression of Ezh2 by inhibiting the <i>miR124</i>-mediated suppression. In developing ENCCs, Ezh2 is a master regulator of 102 core genes underlying ENCC differentiation. Deletion of <i>Gli2</i> or inhibition of Ezh2 favors the neurogenic lineage differentiation of mouse and human ENCCs and rescues the ENS defects of <i>Kif7</i> mutants. In summary, Hedgehog signal, via Kif7-Gli-Ezh2, controls the timely expressions of the core genes to mediate the differentiation of ENCCs.