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The Journal of Neuroscience, July 29, 2009, 29(30):9614-9624; doi:10.1523/JNEUROSCI.2284-09.2009

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Development/Plasticity/Repair
Cyclin D2 Is Critical for Intermediate Progenitor Cell Proliferation in the Embryonic Cortex

Sara B. Glickstein,¹ Julie A. Monaghan,² Hajira B. Koeller,^1,2 Tiffanie K. Jones,³ and M. Elizabeth Ross^1,2

¹Department of Neurology and Neuroscience and ²Graduate Program in Neuroscience, Weill Medical College of Cornell University, New York, New York 10021, and ³Yale University, School of Medicine, New Haven, Connecticut 06510

Correspondence should be addressed to Dr. M. Elizabeth Ross, Department of Neurology and Neuroscience, Weill Medical College of Cornell University, 1300 York Avenue, Box 239, New York, NY 10065. Email: mer2005{at}med.cornell.edu

Expression of cyclins D1 (cD1) and D2 (cD2) in ventricular zone and subventricular zone (SVZ), respectively, suggests that a switch to cD2 could be a requisite step in the generation of cortical intermediate progenitor cells (IPCs). However, direct evidence is lacking. Here, cD1 or cD2 was seen to colabel subsets of Pax6-expressing radial glial cells (RGCs), whereas only cD2 colabeled with Tbr2. Loss of IPCs in cD2^–/– embryonic cortex and analysis of expression patterns in mutant embryos lacking cD2 or Tbr2 indicate that cD2 is used as progenitors transition from RGCs to IPCs and is important for the expansion of the IPC pool. This was further supported by the laminar thinning, microcephaly, and selective reduction in the cortical SVZ population in the cD2^–/–cortex. Cell cycle dynamics between embryonic day 14–16 in knock-out lines showed preserved parameters in cD1 mutants that induced cD2 expression, but absence of cD2 was not compensated by cD1. Loss of cD2 was associated with reduced proliferation and enhanced cell cycle exit in embryonic cortical progenitors, indicating a crucial role of cD2 for the support of cortical IPC divisions. In addition, knock-out of cD2, but not cD1, affected both G₁-phase and also S-phase duration, implicating the importance of these phases for division cycles that expand the progenitor pool. That cD2 was the predominant D-cyclin expressed in the human SVZ at 19–20 weeks gestation indicated the evolutionary importance of cD2 in larger mammals for whom expansive intermediate progenitor divisions are thought to enable generation of larger, convoluted, cerebral cortices.

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Received May 14, 2009; revised June 19, 2009; accepted June 24, 2009.

Correspondence should be addressed to Dr. M. Elizabeth Ross, Department of Neurology and Neuroscience, Weill Medical College of Cornell University, 1300 York Avenue, Box 239, New York, NY 10065. Email: mer2005{at}med.cornell.edu

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