EXOSC10 haploinsufficiency causes primary microcephaly by derepression of Sonic hedgehog signalling

The evolutionarily conserved RNA exosome complex modulates gene expression during development. Mutations in RNA exosome complex subunits have been implicated in various human brain disorders, suggesting that defects in RNA decay are linked to impaired neural development. In our study, we identified de novo variants of EXOSC10 in microcephalic individuals. The patient's phenotype can be replicated by heterozygous conditional knockout of Exosc10 in the developing mouse forebrain. The heterozygous loss of Exosc10 in the developing mouse cortex leads to increased cell cycle exit, with a premature differentiation of radial glial cells to intermediate progenitors and neurons in the embryonic cortex. This premature neurogenesis at the expense of neural stem cell proliferation coincides with a smaller cortical size. RNA sequencing and RNA immunoprecipitation sequencing revealed upregulation of many Sonic hedgehog (Shh) signalling genes. We further show the direct degradation of Shh pathway transcripts such as Scube1 and Scube3 by Exosc10. In Exosc10 mouse mutants, the reduced cortical size could be largely rescued by reducing Shh activity. We propose that increased Shh activity due to Exosc10 deficiency leads to premature neurogenesis and ultimately to microcephaly. These observations offer new insights into the neurodevelopmental role of Exosc10 and highlight the dosage-dependent regulation of Shh signalling by Exosc10 in cortical development.