Centrosome anchoring regulates progenitor properties and cortical formation

Abstract

SUMMARY Radial glial progenitors (RGPs) represent the major neural progenitors for generating neurons and glia in the developing mammalian cerebral cortex 1 - 3 . They position their centrosomes away from the nucleus at the ventricular zone surface 4 - 7 . However, the molecular basis and precise function of this highly unique and characteristic subcellular organization of the centrosome remain largely unknown. Here we show that apical membrane anchoring of the centrosome controls the mechanical properties of mouse cortical RGPs and consequently their mitotic behaviour and cortical size and formation. Mother centriole in RGPs specifically develops distal appendages to anchor to the apical membrane. Selective removal of Centrosomal protein 83 (CEP83) eliminates mother centriole distal appendages and disrupts centrosome apical membrane anchorage, resulting in microtubule disorganization and apical membrane stretching and stiffening. It activates mechanically-sensitive Yes-associated protein (YAP) and promotes excessive RGP proliferation and subsequent intermediate progenitor overproduction, leading to the formation of an enlarged cortex with abnormal folding. Simultaneous elimination of YAP suppresses cortical enlargement and folding caused by CEP83 removal. Together, these results uncover a previously unknown role of the centrosome in regulating the mechanical features of neural progenitors, and the size and configuration of the mammalian cerebral cortex.

Parallel in vivo analysis of large-effect autism genes implicates cortical neurogenesis and estrogen in risk and resilience

“…For example, here we observe chd8 Xenopus mutants have, on average, smaller telencephalons, whereas patients with CHD8 haploinsufficiency exhibit macrocephaly (Ji et al, 2015;Evers et al, 2017;van Bon et al, 2016;Yasin et al, 2019;Bernier et al, 2014;O'Roak et al, 2012a;Ye et al, 2015). It is well-established that affecting NPC biology during neurogenesis can lead to increased or decreased brain size (Shao et al, 2020;Faheem et al, 2015;Lasser et al, 2018). For example, a delay in differentiation could cause a relative increase in NPCs that could resolve as a larger brain.…”

LPA signaling acts as a cell-extrinsic mechanism to initiate cilia disassembly and promote neurogenesis

“…Previous studies showed that targeted deletion of Lpar1 results in ~50% neonatal lethality, impaired suckling in neonatal pups, and adult Lpar1 knockout survivors showing reduced size and craniofacial dysmorphism 32 . Importantly, both Lpar1 KO and Yap cKO mice showed obvious neurogenesis defects during cerebral cortex development, which was closely related to ciliogenesis 53 – 56 . We next examined the distribution patterns of NPCs in the developing cortex of Lpar1- knockout mice 32 .…”

“…NPCs and other cells in the cortex were isolated in accordance with the manufacturer’s instructions (130-092-628, Miltenyi Biotec). Isolated cells were resuspended in Dulbecco’s modified Eagle medium (DMEM) containing glutamine, penicillin/streptomycin, sodium pyruvate, l -cysteine and B27, and plated onto coverslips coated with poly-lysine in 24-well plates 56 . The cultures were maintained at 37 °C with 5% CO 2 .…”

The Multifaceted Roles of Primary Cilia in the Development of the Cerebral Cortex

“…Cep83 encodes a centrosomal protein that is crucial for the assembly of distal appendages leading to cilia initiation ( Joo et al, 2013 ; Tanos et al, 2013 ). Its conditional inactivation using an Emx1Cre driver line, that mediates Cre expression in the dorsal telencephalon from E9.5, impaired the anchoring of the centrosome to the apical membrane of RGCs and the formation of the primary cilium ( Shao et al, 2020 ). Due to an increased stem cell pool, these defects resulted in an enlarged cortex which formed a prominent fold in the cingulate cortex.…”