Microcephaly Proteins Wdr62 and Aspm Define a Mother Centriole Complex Regulating Centriole Biogenesis, Apical Complex, and Cell Fate

Abstract

SUMMARY Mutations in several genes encoding centrosomal proteins dramatically decrease the size of the human brain. We show that Aspm and Wdr62 interact genetically to control brain size, with mice lacking Wdr62, Aspm or both showing gene dose-related centriole duplication defects that parallel the severity of the microcephaly, and increased ectopic basal progenitors, suggesting premature delamination from the ventricular zone. Wdr62 and Aspm localize to the proximal end of the mother centriole and interact physically, with Wdr62 required for Aspm localization, and both proteins, as well as microcephaly protein Cep63, required to localize CENPJ/CPAP/Sas-4, a final common target. Unexpectedly, Aspm and Wdr62 are required for normal apical complex localization and apical epithelial structure, providing a plausible unifying mechanism for the premature delamination and precocious differentiation of progenitors. Together, our results reveal links between centrioles, apical proteins, and cell fate, and illuminate how alterations in these interactions can dynamically regulate brain size.

Once and only once: mechanisms of centriole duplication and their deregulation in disease

“…Currently, mutations in twelve genes encoding centrosome-localized proteins have been shown to cause MCPH and at least eight of these have established roles in centriole duplication (Table 2) 188–190 . This suggests that defects in centriole biogenesis may be an underlying cause of neurogenesis defects in MCPH 191 . Consistently, microcephaly causing mutations in PLK4 and CPAP have been shown to impair centriole biogenesis and depletion of proteins required for centriole duplication reduces the brain size of mice 32,111–113,192–194 .…”

“…In agreement with this view, spindle orientation defects have been observed in brain organoids [G] and mice with MCPH-causing mutations in CDK5RAP2 196,197 . While this mechanism is appealing, randomizing spindle orientation in mouse neuroepithelial progenitors does not affect the rate at which neurons are produced 198 , and defects in mitotic spindle orientation were not observed in the microcephalic brains of some mouse models 191 .…”

Genetics and mechanisms leading to human cortical malformations

“…In mice lacking Wdr62, Aspm, or both, gene dose-related centriole duplication defects were detected during cell division that parallel the severity of the microcephaly. Disrupted apical complexes and increased ectopic basal progenitors are also observed, suggesting premature delamination of RGCs from the VZ [257]. These proteins, share a common localization during interphase at mother centrioles, where they physically interact, and with other microcephaly proteins converge on CENPJ/CPAP/Sas-4 as a final common target [257].…”

“…Disrupted apical complexes and increased ectopic basal progenitors are also observed, suggesting premature delamination of RGCs from the VZ [257]. These proteins, share a common localization during interphase at mother centrioles, where they physically interact, and with other microcephaly proteins converge on CENPJ/CPAP/Sas-4 as a final common target [257]. WDR62 mutations can also give rise to PMG [258][259][260], whereas ASPM mutations have been associated with anterior predominant pachygyria and simplified gyral pattern [261,262].…”

Aspm knockout ferret reveals an evolutionary mechanism governing cerebral cortical size

“…While genes essential for cortical developmental expansion have been identified from the genetics of human primary microcephaly (“small head”, associated with reduced brain size and intellectual disability) 1 , studies of these genes in mice, whose smooth cortex is one thousand times smaller than that of humans, have provided limited insight. Mutations of abnormal spindle-like microcephaly-associated ( ASPM ), the most common recessive microcephaly gene, reduce cortical volume by ≥50% in humans 2–4 , but have little effect in mice 5–9 , likely reflecting evolutionarily divergent functions of ASPM 10,11 . We used genome editing to create a germline knockout (KO) of Aspm in the ferret ( Mustela putorius furo ), a species with a larger, gyrified cortex and greater neural progenitor cell (NPC) diversity 12–14 than mice, and closer Aspm protein sequence homology to human.…”