Too much BMPR-IB (right) causes widespread cell death.

McKay/CSH

Seemingly confounding and contradictory, the ability of bone morphogenetic proteins (BMPs) to promote both proliferation and terminal differentiation (and even apoptosis!) of neuronal stem cells—to both expand and limit precursor cell numbers—now makes perfectly good sense. At least it does in light of the conclusions drawn by Ronald McKay, David Panchision, and colleagues (National Institutes of Health, Bethesda, MD), who postulate a mechanism by which BMP ligands control both the production and fate of neural precursor cells.

Panchision attributes this “dynamic process” to the sequential and linked expression and function of two BMP receptors, BMPR-IA and BMPR-IB. In this model, “the BMP-mediated induction of receptor IB accounts for features of stem cell proliferation, identity, differentiation, and death,” says McKay.

Expression of mutant BMP receptors in CNS stem cells in vitro and in transgenic mice led to the startling discovery of a “feed-forward” mechanism. Activation of the BMPR-IA receptor early in development promotes proliferation of neural precursor cells and determines their dorsal identity. But BMPR-IA also induces the expression of Bmpr-1b. BMPR-IB activation then mediates mitotic arrest, resulting in either apoptosis (early in development, perhaps to control cell numbers) or terminal differentiation (later in development, for those cells that are left). Additional competence signals must be required to interpret the BMPR-IB signal into an apopototic or differentiation response.

An induction–termination sequence could, suggests Panchision, be a general property of signaling in stem cells. It is unclear whether this self-limiting sequential mechanism, which dead-ends at terminal differentiation or cell death, could be reactivated on demand to regenerate tissues, say during wound healing or limb amputation. McKay envisions using knowledge of the linked receptor model to control stem cell proliferation and differentiation, with an eye toward potential applications in cell therapy and cancer therapeutics. ▪

Reference:

Panchision, D.M., et al.
2001
.
Genes Dev.
15
:
2094
–2110.