Arachidonic acid incorporation into phosphatidylinositol by LPLAT11/MBOAT7 ensures radial glial cell integrity in developing neocortex

Abstract

AbstractArachidonic acid, a vital polyunsaturated fatty acid in brain development, is enriched in phosphatidylinositol (PI). The arachidonic acyl chain in PI is introduced by lysophospholipid acyltransferase 11 (LPLAT11)/membrane-bound O-acyltransferase 7 (MBOAT7), the loss of which causes cortical atrophy in humans and mice. Here, we show that LPLAT11 deficiency impaired indirect neurogenesis in the developing neocortex, resulting in fewer layer II-V neurons. LPLAT11-deficient radial glial cells had defects in differentiation into intermediate progenitor cells and increased apoptosis. Prior to these anomalies, LPLAT11 deficiency caused a fragmentation of the Golgi apparatus, accompanied by impaired apical trafficking of E-cadherin, and deregulated apical detachment. Moreover, impaired PI acyl chain remodeling led to a decreased amount of PI(4,5)P2, leading to Golgi apparatus fragmentation. Thus, these results clarify the underlying mechanism of cortical atrophy by LPLAT11 deficiency and highlight the critical role of arachidonic acid in PI in the integrity of radial glial cells.