Time is of the essence: the molecular mechanisms of primary microcephaly

Abstract

Primary microcephaly is a brain growth disorder characterized by a severe reduction of brain size and thinning of the cerebral cortex. Many primary microcephaly mutations occur in genes that encode centrosome proteins, highlighting an important role for centrosomes in cortical development. Centrosomes are microtubule organizing centers that participate in several processes, including controlling polarity, catalyzing spindle assembly in mitosis, and building primary cilia. Understanding which of these processes are altered and how these disruptions contribute to microcephaly pathogenesis is a central unresolved question. In this review, we revisit the different models that have been proposed to explain how centrosome dysfunction impairs cortical development. We review the evidence supporting a unified model in which centrosome defects reduce cell proliferation in the developing cortex by prolonging mitosis and activating a mitotic surveillance pathway. Finally, we also extend our discussion to centrosome-independent microcephaly mutations, such as those involved in DNA replication and repair.

Tissue-wide genetic and cellular landscape shapes the execution of sequential PRC2 functions in neural stem cell lineage progression

“…Despite the diverse genetic causes, microcephaly phenotypes often converge to trigger p53 activation and apoptosis in dividing RGPs and/or nascent neurons. In such cases, genetic deletion of Trp53 rescues the microcephaly phenotype ( 41 – 44 ). We noted the presence of p53-related GO terms in several modules of the STRING network (data table S1).…”

Microcephaly-associated WDR62 mutations hamper Golgi apparatus-to-spindle pole shuttling in human neural progenitors

“…By consensus, MCPH is thought to be a consequence of neural progenitor depletion/premature differentiation (Jayaraman et al, 2018; Phan & Holland, 2021). For instance, in MCPH3 (caused by mutations in CDK5RAP2) (Lancaster et al, 2013), MCPH5 (ASPM) (R. Li et al, 2017), and MCPH6 (CENPJ) (Bond et al, 2005), neural progenitors at the Ventricular Zone (VZ)/Sub-Ventricular Zone (SVZ) lose their broad proliferative capacity impacting final brain architecture and size (Gabriel et al, 2020; Phan & Holland, 2021). For this reason, we sought to determine whether the WDR62 mutation might impact NES cell features.…”

“…Mutations in genes involved in the regulation of mitotic progression in neural progenitor cells (NPCs) have been identified in several types of MCPH (Phan & Holland, 2021; Thornton & Woods, 2009), a genetically heterogeneous disorder characterized by occipito-frontal circumference 3-4 standard deviations below the mean of ethnically-, age-, and sex-matched controls (Woods & Parker, 2013). Intriguingly, many of the genes associated with MCPH encode centrosomal or pericentriolar proteins, while others participate in mitotic spindle organization and mitotic progression (Jayaraman et al, 2018; Phan & Holland, 2021).…”

Biallelic germline mutations in MAD1L1 induce a syndrome of aneuploidy with high tumor susceptibility

“…Human diseases characterized by chromosomal instability are typically associated to mutations in genes related to cell division. Mutations in genes associated with centrosome and microtubule dynamics, chromosome morphology, and kinetochore functions affect the majority of patients with primary microcephaly ( 3 ), and alteration of different cohesin subunits and associated regulators results in a variety of pathologies known as cohesinopathies ( 4 ). Aneuploidy, however, is only occasionally observed in these pathologies ( 4 ).…”