Andrew Koff: Function of p21 During Oligodendrocyte Differntiation

The first practical hint that CDK inhibitors might play a role in differentiation independent of cell cycle exit was our observation in oligodendrocyte progenitor cells that p27 was required for growth arrest and p21 for differentiation. Other groups have since found similar relationships in other cell types, but in no case was the nature of this role well understood. In part this is because of the difficulty in isolating and manipulating gene expression in primary cells in which such roles are apparent. However, now with better isolation, manipulation and culture systems we think this fascinating area can be studied experimentally to address with whom these CDK inhibitors interact, how these interactions affect the transcriptional program of differentiation or fate determination, and ultimately, how CDK inhibitors act to prevent CDK activity and whether CDK activity interferes with transcription. There are two venues where we are interested in following-up this question: one, the original OPC differentiation paradigm where we have generated temperature-sensitive immortalized cell variants that can retain their differentiation potential upon shift to restrictive temperature, and two using mouse mesenchymal stem cells to probe the cell cycle programs upon differentiation to adipocyte and muscle lineages.

Figure 1 Enlarge Image Distinct roles of CDK inhibitors during oligodendrocyte differentiation. (Top left) Immunoblots. CDK inhibitors are shown in each panel as indicated on the righ in progentior cells (OPC) and differentiated cells (oligo). (Middle) Cell morphology after the switch to differentiation conditions. Genotypes are indicated in each panel. (Right) BrdU incorporation. DAPI and BrdU positive cells are shown for each genotype after the switch to differentiation media. (Bottom) We suggest the model that p27 plays a role in growth arrest and p21 in differentiation from the data in the top panel.