Fig. 8. Mechanism of PV loss in the cD2^−/− MGE.

(A) Deficits in PV interneuron production occur in early and late MGE populations. The proportion of PV+ cells in layer II-III somatosensory cortex that is also labeled by BrdU injected at E13.5 (n=2 per genotype) or E14.5–15.5 (n=5 per genotype) is significantly reduced in cD2^−/− mice, whereas the proportion of SSN+ cells generated at any age is the same in cD2^−/− and WT littermates. *, P<0.05; **, P<0.002. (B–D) Model of D cyclin roles in the MGE. cD2 normally suppresses p27 levels more strongly than does cD1, requiring more p27 to accumulate before cells can exit the cycle. cD2 also promotes phosphorylation of Rb (pRb), facilitating progression through G1 phase and perhaps influencing downstream gene transcription. cD2 support of SVZ divisions promotes the balanced production of SSN+ and PV+ interneurons. (C) In the absence of cD2, constraints on p27 are lifted and pRb levels fall, hastening cell cycle exit and leaving the proportion of SSN+ neurons unchanged or slightly increased, while disproportionately fewer PV+ interneurons are generated. (D) Loss of cD1 induces cD2 in the VZ, which inhibits p27 and promotes pRb. Divisions continue in both the VZ and SVZ, although they may be slower overall. This leads to fewer rounds of division and reduced total neuronal numbers, but preserved SSN+ and PV+ neuron densities in cD1^−/− brains.