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

In this review, Phan et al. discuss the different models that have been proposed to explain how centrosome dysfunction impairs cortical development, and 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. Last, they also extend their discussion to centrosome-independent microcephaly mutations, such as those involved in DNA replication and repair 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.

Automated summary

This review explores different models on how centrosome dysfunction affects cortical development, emphasizing that centrosome defects reduce cell proliferation in the developing cortex by prolonging mitosis. It also discusses microcephaly mutations unrelated to centrosomes, such as those involved in DNA replication and repair.