Ventral midbrain (VM) dopaminergic (DA) neurons project to the dorsal striatum via the nigrostriatal pathway to regulate voluntary movements. The progressive degeneration of this DA pathway causes the motor dysfunction of Parkinsonís disease (PD). Despite recent progress in the understanding of VM DA neurogenesis, the factors regulating nigrostriatal pathway development remain largely unknown.
The bone morphogenetic protein (BMP) family of proteins, which signal via a canonical Smad 1/5/8 signalling pathway, regulate neurite growth in the developing nervous system, and may contribute to nigrostriatal pathway development. Two related members of the bone morphogenetic protein (BMP) family, BMP2 and growth/differentiation factor (GDF) 5, have been shown to have neurotrophic effects on midbrain DA neurons both in vitro and in vivo, including the promotion of neurite growth, and may function to regulate VM DA neuronal development. However, the molecular (signaling pathway(s)) and cellular (direct neuronal or indirect via glial cells) mechanisms of their effects on DA neurons are unknown.
Using the SH-SH5Y human neuronal cell line, and primary cultures of embryonic rat VM, as models of human midbrain DA neurons, we examined the hypothesis that canonical Smad 1/5/8 signalling mediates the effects of BMP2 and GDF5 on the development of VM DA neurons. By activating, modulating and/or inhibiting various components of the BMP-Smad signalling pathway, this research demonstrated that GDF5- and BMP2-induced neurite outgrowth from midbrain DA neurons is dependent on BMP type I receptor activation of the Smad signalling pathway. Furthermore, the characterisation of the temporal expression profiles of endogenous BMP receptors (BMPRs) in the developing and adult rat VM and striatum supported the potential involvement of BMP2 and GDF5 in the regulation of nigrostriatal pathway development.