Abstract
Phosphatidylinositol (PI) is highly enriched in arachidonic acid, an essential polyunsaturated fatty acid for brain development. This enrichment is mediated by the phospholipid remodeling enzyme lysophospholipid acyltransferase 11 (LPLAT11), also known as membrane-bound O-acyltransferase 7 (MBOAT7), whose deficiency causes microcephaly in both humans and mice. Here, we show that Mboat7 deficiency impairs indirect neurogenesis in the developing neocortex by compromising radial glial cell (RGC) integrity, resulting in fewer layer II-V neurons. Mboat7-deficient RGCs exhibited decreased proliferation, impaired differentiation into intermediate progenitor cells, and increased apoptosis. These defects were preceded by Golgi apparatus rounding, reduced apical E-cadherin expression, and dysregulated apical detachment of RGCs. Moreover, the Mboat7-deficient cortex displayed reduced PI(4,5)P2 levels, and pharmacological inhibition of PI(4,5)P2 synthesis recapitulated the Golgi rounding observed in Mboat7-deficient RGCs. These findings suggest that compromised RGC integrity due to reduced PI(4,5)P2 levels, resulting from decreased arachidonic acid-containing PI, underlies the microcephaly associated with MBOAT7 deficiency.