Bone Morphogenetic Protein Receptors in the Nervous System: Neurotrophic Functions with Emphasis on Catecholaminergic Neurons

Members of the transforming growth factor-β (TGF-β) superfamily exhibit a range of effects on a host of different cell types. They signal through heteromeric complexes of serine/threonine kinase receptors of type I and type II. Gene targeted mutations of both factors and receptors have revealed that many of them are involved in early embryonic development. This thesis examines the receptors for this superfamily in the nervous system, especially bone morphogenetic protein receptor type II (BMPR-II). It was cloned from chicken nervous tissue, and its and other receptors’ expression in peripheral ganglia, spinal cord and brain of chicken, rat and mouse were examined. BMPR-II, ActR-II and ActR-IA were abundantly expressed throughout development in the nervous system, however with temporal regulation. One ligand of BMPR-II, BMP-7, was found to act synergistically with NT-3 and GDNF on subsets of peripheral neurons to promote survival and neurite outgrowth. A knock-in mouse was generated, encoding a truncated form of BMPR-II coupled to the endogenous tyrosine hydroxylase (TH) gene with an internal ribosome entry site (IRES). For ES-cell selection, a neomycin resistance gene was incorporated into the construct. Homozygous mice carrying the knock-in allele exhibited a small, hypokinetic phenotype. Levels of dopamine, noradrenaline and serotonin were measured, and the catecholamines were found to be lowered, dopamine as much as 97% in the caudate nucleus. The low catecholamine levels may not be an effect of the truncated BMPR-II, but rather a consequence of the knock-in construct reducing TH transcriptional rate. The TH hypomorphic mouse strain generated could find use as a model for catecholamine impaired systems, as seen in Parkinson’s disease