The loss of Bmi-1, the researchers find, leaves mice deficient in stem cell capacity. The mice survive using only restricted progenitor cells that are limited in both the types of cells that they can generate and the numbers of divisions in which they can do so. The resulting depletion in cells leads to growth and neurological defects, and early death.
Earlier work had established that Bmi-1, via its repression of the cell cycle inhibitor p16, is required for the proliferation of hematopoietic stem cells (HSCs). The Michigan group found a similar phenomenon with stem cells in the central nervous system, at least after birth, and found that the cause was reduced proliferation rather than increased cell death. But after differentiation factors were added, the difference disappeared. Now, both cells with and without Bmi-1 continued to proliferate.
There are two situations in which an explanation requires more than just Bmi-1 and p16. Prenatally, something other than Bmi-1 must be capable of repressing p16 expression. In the restricted progenitors, meanwhile, Bmi-1 is no longer needed because the cell cycle is now insensitive to elevated levels of p16. Future studies will be focused on understanding this difference in sensitivity, and testing downstream of Bmi-1 for pathways unrelated to p16. ▪