MCPH1 regulates the neuroprogenitor division mode by coupling the centrosomal cycle with mitotic entry through the Chk1–Cdc25 pathway

Abstract

Primary microcephaly 1 is a neurodevelopmental disorder caused by mutations in the MCPH1 gene, whose product MCPH1 (also known as microcephalin and BRIT1) regulates DNA-damage response. Here we show that Mcph1 disruption in mice results in primary microcephaly, mimicking human MCPH1 symptoms, owing to a premature switching of neuroprogenitors from symmetric to asymmetric division. MCPH1-deficiency abrogates the localization of Chk1 to centrosomes, causing premature Cdk1 activation and early mitotic entry, which uncouples mitosis and the centrosome cycle. This misorients the mitotic spindle alignment and shifts the division plane of neuroprogenitors, to bias neurogenic cell fate. Silencing Cdc25b, a centrosome substrate of Chk1, corrects MCPH1-deficiency-induced spindle misalignment and rescues the premature neurogenic production in Mcph1-knockout neocortex. Thus, MCPH1, through its function in the Chk1-Cdc25-Cdk1 pathway to couple the centrosome cycle with mitosis, is required for precise mitotic spindle orientation and thereby regulates the progenitor division mode to maintain brain size.

Promoter hijack reveals pericentrin functions in mitosis and the DNA damage response

“…23,29 Current models suggest that pericentrin interacts with Mcph1 and thus affects Chk1 signaling to Cdk1. 29,36 To explore this idea, we tested the genetic interactions between Pcnt and Mcph1 by targeting Mcph1 in our Pcnt Δ/Δ cells using a previously published strategy. 32 Southern blot analysis confirmed this targeting (Fig.…”

“…43 Recent mouse work supports an impact of Mcph1 deficiency on centrosomal Chk1, suggesting that pericentrin may affect Chk1 at the centrosome. 36 If the key controls on Chk1 depend on its activation through a nuclear-cytosolic/centrosomal feedback loop, 44 localization of even a small fraction of Chk1 within the PCM may be a mechanism by which Mcph1 and pericentrin determine its interactions with its regulators.…”

CPAP promotes timely cilium disassembly to maintain neural progenitor pool

“…For example, loss of MCPH1 results in a shorter G1 phase of the cell cycle through premature mitotic entry. As a result, the centrosomes do not have sufficient time to mature before the onset of division (Gruber et al , 2011). Likewise, loss of CDK5RAP2 directly affected centrosome maturation and thus immature centrosomes accumulate less PCM (Thornton & Woods, 2009).…”

Chromosome Dynamics during Mitosis

“…A more recent study using Xenopus egg extracts has provided evidence that human MCPH1 indeed acts as a highly specific and potent inhibitor of condensin II, but not of condensin I (Yamashita et al 2011). MCPH1 is ubiquitously expressed, and MCPH1-knockout mice are viable, albeit displaying microcephaly (Gruber et al 2011). Why MCPH1 mutations cause specific developmental defects in the brain, but not in other tissues, is an interesting topic for future studies.…”