Bone morphogenetic proteins and their receptors: potential functions in the brain.

Transforming growth factors-beta (TGF-betas), activins, and bone morphogenetic proteins (BMPs) comprise an evolutionarily well-conserved group of proteins controlling a number of cell differentiation, cell growth, and morphogentic processes during development. The superfamily of TGFbeta-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 different responses to these factors. Recent developments have revealed that TGFbetas, activins, and BMPs selectively signal to the responding cells via different hetero-oligomeric complexes of type I and type II serine/threonine kinase receptors. The adult brain exhibits specific expression patterns of some of these receptors suggesting neuronal functions 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 osteogenic protein-1 (OP-1/BMP-7), BMP-2, and BMP-4 as well as activins may serve 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 BMPR-II and ActR-I to sense the presence of BMPs. This may form a system parallel to the neurotrophin Trk tyrosine kinase receptors regulating neuroplasticity and brain repair. The presence of BMPs in brain is not well studied, but preliminary in situ data indicate that the BMP relatives growth/differentiation factor (GDF)-1 and GDF-10 are distinctly but differentially expressed at high levels in neurons expressing BMPR-II and ActR-I. The receptors mediating responses to these two GDFs remain, however, to be defined. Finally, recent data show that the signal from the activated type I serine/threonine kinase receptor is directly transduced to the nucleus by Smad proteins that become incorporated into transcriptional complexes. Preliminary in situ hybridization observations demonstrate the existence of different Smad mRNAs. It is concluded that BMPs and their signaling systems may comprise a novel pathway for control of neural activity and offer means for pharmacological interventions rescuing brain neurons.