Figure 1.

The roles of specific microcephaly proteins in normal proliferation and the effects of their disruption. (A) EG5 (blue and tan coils) is a plus-end-directed microtubule motor protein that pushes apart the duplicated centrosomes to create a bipolar mitotic spindle in prophase and prometaphase, allowing for separation of sister chromatids. (A′) In the absence of EG5 activity, the centrosomes fail to separate, resulting in the formation of a monoaster, which triggers mitotic arrest that can lead to apoptosis. (B) ASPM (green octagon) is a microtubule minus-end-associated protein found at mitotic spindle poles that has been implicated in both mediating symmetric cell divisions (indicated by same colored cells) and orienting the cell division plane (dotted line) in neural stem and progenitor cells. (B′) The absence of ASPM creates more asymmetric divisions (indicated by different colored cells) and altered division planes (top vs. bottom), both of which can promote differentiation over continued proliferation. (C) CDK6 (red octagon) associates with mitotic centrosomes in the cell’s (purple) nucleus (blue), where it may mediate centrosome duplication, spindle assembly, or cellular motility (indicated by dotted lines and arrows). (C′) The CDK6 mutation associated with mirocephalic patients did not reduce CDK6 (grey polygon) protein levels but rather altered its function and behavior such that it no longer associated with centrosomes, which led to supernumerary centrosomes, inappropriate mitotic spindle alignment, abnormal cellular polarity, and reduced cell motility. (D) Endogenous, replication-associated DNA damage (lightning bolt) activates the DNA damage response protein ATR, which recognizes single-stranded DNA coated by RPA (orange circles) at stalled replication forks. Activated ATR can promote G₂/M arrest by barring mitotic entry through preventing CDK1/CDC2 activation and by targeting CEP63 to block assembly of the mitotic spindle. (D′) Absence of ATR function limits DNA repair while also permitting CGNPs with DNA damage to enter mitosis. Progression through mitosis exacerbates DNA damage leading to severe chromosomal aberrations. Overwhelming DNA damage causes ATM to activate p53, resulting in widespread apoptosis of CGNPs.