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

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Abstract

Ventral midbrain (VM) dopaminergic (DA) neurons project to the dorsal striatum via the nigrostriatal pathway to regulate voluntary movements, and their loss leads to the motor dysfunction seen in Parkinson’s 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 regulates neurite growth in the developing nervous system and may contribute to nigrostriatal pathway development. Two related members of this family, BMP2 and growth differentiation factor (GDF)5, have neurotrophic effects, including promotion of neurite growth, on cultured VM DA neurons. However, the molecular mechanisms regulating their effects on DA neurons are unknown. By characterising the temporal expression profiles of endogenous BMP receptors (BMPRs) in the developing and adult rat VM and striatum, this study identified BMP2 and GDF5 as potential regulators of nigrostriatal pathway development. Furthermore, through the use of noggin, dorsomorphin and BMPR/Smad plasmids, this study demonstrated that GDF5- and BMP2-induced neurite outgrowth from cultured VM DA neurons is dependent on BMP type I receptor activation of the Smad 1/5/8 signalling pathway.

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Abbreviations

6-OHDA:

6-Hydroxydopamine

BMP(s):

Bone morphogenetic protein(s)

BMPR(s):

Bone morphogenetic protein receptor(s)

caBMPRIb:

Constitutively active BMPRIb

CNS:

Central nervous system

DA:

Dopaminergic/dopamine

DIV:

Day(s) in vitro

E:

Embryonic day

FCS:

Foetal calf serum

GDF(s):

Growth differentiation factor(s)

GDNF:

Glial cell line-derived neurotrophic factor

N:

Number of repetitions

P:

Post-natal day

PBS:

Phosphate-buffered saline

PD:

Parkinson’s disease

RT-QPCR:

Quantitative real-time PCR

RT-PCR:

Reverse transcriptase-polymerase chain reaction

SC:

Spinal cord

SNpc:

Substantia nigra pars compacta

TGF:

Transforming growth factor

TH:

Tyrosine hydroxlase

VM:

Ventral midbrain/mesencephalon

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Acknowledgments

The authors declare no conflict of interest. This work was supported by grant support from the Irish Research Council (SVH/AS/G’OK), the Health Research Board of Ireland (HRA/2009/127) (GO’K/AS) and Science Foundation Ireland (10/RFP/NES2786) (GO’K).

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The authors declare that there are no conflicts of interest.

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Authors and Affiliations

  1. Department of Anatomy and Neuroscience, Biosciences Institute, University College Cork, Cork, Ireland

    Shane V. Hegarty, Louise M. Collins, Aisling M. Gavin, Sarah L. Roche, Aideen M. Sullivan & Gerard W. O’Keeffe

  2. Molecular Biosciences Research Division, School of Biosciences, Life Sciences Building, Museum Avenue, Cardiff, CF10 3AT, UK

    Sean L. Wyatt

  3. The Irish Centre for Fetal and Neonatal Translational Research (INFANT), Cork University Maternity Hospital, Cork, Ireland

    Gerard W. O’Keeffe

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  1. Shane V. Hegarty
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  2. Louise M. Collins
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  3. Aisling M. Gavin
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  4. Sarah L. Roche
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  6. Aideen M. Sullivan
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  7. Gerard W. O’Keeffe
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Correspondence to Aideen M. Sullivan or Gerard W. O’Keeffe.

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Aideen M. Sullivan and Gerard W. O’Keeffe have contributed equally to this work.

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Experimental primers and hybridisation probes (TIFF 3661 kb)

12017_2014_8299_MOESM2_ESM.tif

Noggin and dorsomorphin prevent the promotion of SH-SH5Y neurite growth by BMP2 and GDF5. (a) Total neurite length of noggin- or dorsomorphin-pre-treated and/or BMP2- or GDF5-treated (daily for 4 DIV) SH-SY5Y cells, as indicated (*** P < 0.001 vs. control; ANOVA with post hoc Tukey’s test; 20 images analysed for each group per experiment; N = 3 experiments). Data are expressed as mean ± SEM. (b) Representative photomicrographs of noggin pre-treated and/or BMP2- or GDF5-treated SH-SY5Y cells, as indicated, immunocytochemically stained for β-actin. Scale bar = 100 μm (TIFF 4240 kb)

12017_2014_8299_MOESM3_ESM.tif

Heparinase III does not affect the promotion of SH-SH5Y neurite growth by BMP2 and GDF5. (a) Total neurite length of Heparinase III-pre-treated and/or BMP2- or GDF5-treated (daily for 4 DIV) SH-SY5Y cells, as indicated (*** P < 0.001 vs. control; ANOVA with post hoc Tukey’s test; 20 images analysed for each group per experiment; N = 3 experiments). Data are expressed as mean ± SEM. (b) Representative photomicrographs of Heparinase III-pre-treated and/or GDF5-treated SH-SY5Y cells, as indicated, immunocytochemically stained for β-actin. Scale bar = 100 μm (TIFF 1711 kb)

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Hegarty, S.V., Collins, L.M., Gavin, A.M. et al. Canonical BMP–Smad Signalling Promotes Neurite Growth in Rat Midbrain Dopaminergic Neurons. Neuromol Med 16, 473–489 (2014). https://doi.org/10.1007/s12017-014-8299-5

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