BONE MORPHOGENETIC PROTEINS AND THEIR RECEPTORS - POTENTIAL FUNCTIONSIN THE BRAIN

Transforming growth factors-beta (TGF-beta s), activins, and bone morp hogenetic proteins (BMPs) comprise an evolutionarily well-conserved gr oup of proteins controlling a number of cell differentiation, cell gro wth, and morphogentic processes during development. The superfamily of TGF beta-related genes include over 25 members in mammals several of which are expressed in the growing nervous system and serve important functions in regionalizing the early CNS. Cultured nerve cells show di fferent responses to these factors. Recent developments have revealed that TGF beta s, activins, and BMPs selectively signal to the respondi ng cells via different hetero-oligomeric complexes of type I and type II serine/threonine kinase receptors. The adult brain exhibits specifi c expression patterns of some of these receptors suggesting neuronal f unctions not only during development but also in the mature brain. In particular, the brain is expressing high levels of bone morphogenetic protein receptor type II (BMPR-II), activin receptor type I (ActR-I), and activin receptor type IIA (ActR-II). This indicates that osteogeni c protein-1 (OP-1/BMP-7), BMP-2, and BMP-4 as well as activins may ser ve functions for brain neurons. Expression of the receptors partially overlaps in populations of neurons and has been shown to be regulated by brain lesions. This suggests that brain neurons may use receptors B MPR-II and ActR-I to sense the presence of BMPs. This may form a syste m parallel to the neurotrophin Trk tyrosine kinase receptors regulatin g neuroplasticity and brain repair. The presence of BMPs in brain is n ot well studied, but preliminary in situ data indicate that the BMP re latives growth/differentiation factor (GDF)-1 and GDF-10 are distinctl y but differentially expressed at high levels in neurons expressing BM PR-II and ActR-I. The receptors mediating responses to these two GDFs remain, however, to be defined. Finally, recent data show that the sig nal from the activated type I serine/threonine kinase receptor is dire ctly transduced to the nucleus by Smad proteins that become incorporat ed into transcriptional complexes. Preliminary in situ hybridization o bservations demonstrate the existence of different Smad mRNAs. It is c oncluded that BMPs and their signaling systems may comprise a novel pa thway for control of neural activity and offer means for pharmacologic al interventions rescuing brain neurons. (C) 1998 Wiley-Liss, Inc.