Roles for the TGFβ Superfamily in the Development and Survival of Midbrain Dopaminergic Neurons

Abstract

The adult midbrain contains 75% of all dopaminergic neurons in the CNS. Within the midbrain, these neurons are divided into three anatomically and functionally distinct clusters termed A8, A9 and A10. The A9 group plays a functionally non-redundant role in the control of voluntary movement, which is highlighted by the motor syndrome that results from their progressive degeneration in the neurodegenerative disorder, Parkinson's disease. Despite 50 years of investigation, treatment for Parkinson's disease remains symptomatic, but an intensive research effort has proposed delivering neurotrophic factors to the brain to protect the remaining dopaminergic neurons, or using these neurotrophic factors to differentiate dopaminergic neurons from stem cell sources for cell transplantation. Most neurotrophic factors studied in this context have been members of the transforming growth factor β (TGFβ) superfamily. In recent years, an intensive research effort has focused on understanding the function of these proteins in midbrain dopaminergic neuron development and their role in the molecular architecture that regulates the development of this brain region, with the goal of applying this knowledge to develop novel therapies for Parkinson's disease. In this review, the current evidence showing that TGFβ superfamily members play critical roles in the regulation of midbrain dopaminergic neuron induction, differentiation, target innervation and survival during embryonic and postnatal development is analysed, and the implications of these findings are discussed.

Canonical BMP–Smad Signalling Promotes Neurite Growth in Rat Midbrain Dopaminergic Neurons

“…Crucially, the expression of these BMPRs, both of which are required for canonical BMP-Smad signalling (Miyazono et al 2010;Sieber et al 2009), in the VM from E14 onwards correlates with the timing of the generation of nigrostriatal projections. These data suggest that BMPs, such as BMP2 and GDF5 that are expressed in the developing and adult VM and striatum (Krieglstein et al 1995;O'Keeffe et al 2004b;Storm et al 1994;Chen et al 2003;Jordan et al 1997;Soderstrom and Ebendal 1999;Hegarty et al 2014), may regulate the establishment of nigrostriatal projections from VM DA neurons. In support of this suggestion, the present study has demonstrated that both BMP2 and GDF5 promote neurite outgrowth from E14 VM neurons in culture.…”

“…However, some molecules, such as Ephs and netrin1, have been identified as regulators of nigrostriatal pathway development in recent years (Hegarty et al 2013a; Van den Heuvel and Pasterkamp 2008). In an attempt to identify new candidate molecules and signalling pathways that may be involved in nigrostriatal development, this study focused on two BMPs, GDF5 and BMP2, since both of these factors have been implicated in axonal growth in (Parikh et al 2011;Hazen et al 2011Hazen et al , 2012Phan et al 2010;Niere et al 2006;Lein et al 1995;Hegarty et al 2013a) and have been shown to have neurotrophic effects on VM DA neurons, specifically survivaland neurite growth-promoting effects (O'Keeffe et al 2004a;Reiriz et al 1999;Jordan et al 1997;Sullivan et al 1997;Hegarty et al 2014). Despite these studies, the downstream molecular mechanisms that mediate the effects of GDF5 and BMP2 on VM DA neurons are unknown.…”

“…BMP2 and GDF5 are expressed in the developing rat VM during the period of DA axogenesis, suggesting that they may play a role in this process (Krieglstein et al 1995;O'Keeffe et al 2004b;Storm et al 1994;Chen et al 2003;Jordan et al 1997;Soderstrom and Ebendal 1999;Hegarty et al 2014). In support of such a suggestion, both GDF5 and BMP2 have been shown to promote the survival of rat VM DA neurons (O'Keeffe et al 2004a;Reiriz et al 1999;Jordan et al 1997;Sullivan et al 1997) and induce neurite growth of rat VM DA neurons in vitro (O'Keeffe et al 2004a;Reiriz et al 1999).…”

Targeting bone morphogenetic protein signalling in midbrain dopaminergic neurons as a therapeutic approach in Parkinson's disease

“…Given the lack of efficacy of AAV-NTN to date [21] and the fact GDNF ligands may not be able to signal in the PD brain due to down-regulation of Ret [22], it has recently been suggested that 'better results might be achieved with other trophic factors that are not Ret dependent' and that 'it might also be of value to assess trophic factors in animal models that overexpress α-synuclein prior to initiating translational clinical trials' [21]. Given that BMP ligands have the same efficacy as GDNF in 6-OHDA animal models of PD [18,19], and that their effects on mDA neurons are mediated in a Ret-independent manner through the Smad pathway [34], it will be crucial to determine if BMPR expression or key downstream effector proteins are affected by α-synuclein, and if the BMP ligands can exert neuroprotective effects in the α-synuclein model of PD. It is interesting to note that BMP2 has also recently been shown to up-regulate Nurr1 [86], raising the intriguing possibility that BMP ligands may restore responsiveness to the GDNF ligands, and highlighting the potential for combined neurotrophic factor therapy to protect mDA axons as well as their neuronal soma.…”

“…Several members of the transforming growth factor-β (TGFB) superfamily are potent neurotrophic factors for mDA neurons [18]. These include glial cell line-derived neurotrophic factor (GDNF) and neurturin (NTN), which have been tested in clinical trials [19].…”