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.

Keywords: brain development; centriole; centrosome; cilia; microcephaly.

Figure 1.

Cortical development at different stages in humans and the equivalent time line in mice. (A) As the neural tube develops, it enlarges into three vesicles corresponding to the forebrain, midbrain, and hindbrain regions of the adult brain. At this stage, the neural tube wall has a single layer of neuroepithelial cells (NECs). These cells migrate to the lumen of the neural tube to divide, a phenomenon also known as interkinetic nuclear migration. (B) At the midstage of neurogenesis, apical radial glial cells (aRGCs) that derived from NECs can undergo either symmetric division to expand the progenitor pool size or asymmetric division, giving rise to basal RGCs (bRGCs) or intermediate progenitors (IPs). Note that bRGCs are almost absent in rodents. bRGCs, IPs, and aRGCs will eventually generate postmitotic neurons that migrate toward the pial surface. (VZ) Ventricular zone, (SVZ) subventricular zone, (IZ) intermediate zone, (CP) cortical plate. (C) The fully formed adult cerebral cortex consists of six layers of neurons.

Figure 2.

Centrosome biogenesis cycle. G1 cells contain a single centrosome comprising a pair of centrioles surrounded by the pericentriolar material (PCM). The mature parent centriole is decorated with distal and subdistal appendages, while the immature centriole lacks these structures. In S phase, a single procentriole forms on both parent centrioles. Throughout S and G2 phases, the procentrioles elongate, and in late G2, the two centrosomes separate and undergo PCM expansion. During mitosis, the two centrosomes act to catalyze the assembly of the bipolar microtubule spindle apparatus on which chromosomes are segregated. The mature parent centriole can also dock at the cell membrane and initiate the assembly of a primary cilium in early G1 in the case of dividing cells, or during G0 phase in quiescent cells.

Figure 3.

The molecular genetics of primary microcephaly. (A) Genes implicated in MCPH and MPD classified by functional group and subcellular localization. (B) Schematic of representative centrosome and spindle proteins mutated in microcephaly. Protein domains and regions of interactions are depicted based on studies by Gillingham and Munro (2000), Kohlmaier (2009), Carvalho-Santos et al. (2010), Hatch et al. (2010), Holland et al. (2010), Van Breugel et al. (2011), Issa et al. (2013), Kim et al. (2013), Lin et al. (2013), Sonnen et al. (2013), Arquint et al. (2015), Mori et al. (2015), Chen et al. (2017), and Patwardhan et al. (2018). (SMC-A/B) Structural maintenance of chromosomes (SMC)-like domain A/B, (PBD) polo-box domain, (CR1/2) conserved region 1/2, (CC) coiled-coil region, (STAN) Stil/Ana2 domain, (PISA) present in SAS-6, (TCP) T complex protein 10 domain, (CH) calponin homology domain, (MBD) MKK7β1 binding domain, (JBD) JNK binding domain, (LHD) loop helix domain.

Figure 4.

Cellular processes disrupted in neural progenitor cells by microcephaly mutations in centrosomal proteins. Mutations in genes that encode centrosome proteins have been proposed to cause microcephaly through several mechanisms. This includes deregulating of cell cycle progression, altering spindle orientation, increasing the frequency of chromosome missegregation, disrupting asymmetric centrosome inheritance, and delaying mitotic spindle assembly.