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Wnt5a Regulates Midbrain Dopaminergic Axon Growth and Guidance
During development, precise temporal and spatial gradients are responsible for guiding axons to their appropriate targets. Within the developing ventral midbrain (VM) the cues that guide dopaminergic (DA) axons to their forebrain targets remain to be fully elucidated. Wnts are morphogens that have b...
Autores principales: | , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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Public Library of Science
2011
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3069098/ https://www.ncbi.nlm.nih.gov/pubmed/21483795 http://dx.doi.org/10.1371/journal.pone.0018373 |
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author | Blakely, Brette D. Bye, Christopher R. Fernando, Chathurini V. Horne, Malcolm K. Macheda, Maria L. Stacker, Steven A. Arenas, Ernest Parish, Clare L. |
author_facet | Blakely, Brette D. Bye, Christopher R. Fernando, Chathurini V. Horne, Malcolm K. Macheda, Maria L. Stacker, Steven A. Arenas, Ernest Parish, Clare L. |
author_sort | Blakely, Brette D. |
collection | PubMed |
description | During development, precise temporal and spatial gradients are responsible for guiding axons to their appropriate targets. Within the developing ventral midbrain (VM) the cues that guide dopaminergic (DA) axons to their forebrain targets remain to be fully elucidated. Wnts are morphogens that have been identified as axon guidance molecules. Several Wnts are expressed in the VM where they regulate the birth of DA neurons. Here, we describe that a precise temporo-spatial expression of Wnt5a accompanies the development of nigrostriatal projections by VM DA neurons. In mice at E11.5, Wnt5a is expressed in the VM where it was found to promote DA neurite and axonal growth in VM primary cultures. By E14.5, when DA axons are approaching their striatal target, Wnt5a causes DA neurite retraction in primary cultures. Co-culture of VM explants with Wnt5a-overexpressing cell aggregates revealed that Wnt5a is capable of repelling DA neurites. Antagonism experiments revealed that the effects of Wnt5a are mediated by the Frizzled receptors and by the small GTPase, Rac1 (a component of the non-canonical Wnt planar cell polarity pathway). Moreover, the effects were specific as they could be blocked by Wnt5a antibody, sFRPs and RYK-Fc. The importance of Wnt5a in DA axon morphogenesis was further verified in Wnt5a (−/−) mice, where fasciculation of the medial forebrain bundle (MFB) as well as the density of DA neurites in the MFB and striatal terminals were disrupted. Thus, our results identify a novel role of Wnt5a in DA axon growth and guidance. |
format | Text |
id | pubmed-3069098 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-30690982011-04-11 Wnt5a Regulates Midbrain Dopaminergic Axon Growth and Guidance Blakely, Brette D. Bye, Christopher R. Fernando, Chathurini V. Horne, Malcolm K. Macheda, Maria L. Stacker, Steven A. Arenas, Ernest Parish, Clare L. PLoS One Research Article During development, precise temporal and spatial gradients are responsible for guiding axons to their appropriate targets. Within the developing ventral midbrain (VM) the cues that guide dopaminergic (DA) axons to their forebrain targets remain to be fully elucidated. Wnts are morphogens that have been identified as axon guidance molecules. Several Wnts are expressed in the VM where they regulate the birth of DA neurons. Here, we describe that a precise temporo-spatial expression of Wnt5a accompanies the development of nigrostriatal projections by VM DA neurons. In mice at E11.5, Wnt5a is expressed in the VM where it was found to promote DA neurite and axonal growth in VM primary cultures. By E14.5, when DA axons are approaching their striatal target, Wnt5a causes DA neurite retraction in primary cultures. Co-culture of VM explants with Wnt5a-overexpressing cell aggregates revealed that Wnt5a is capable of repelling DA neurites. Antagonism experiments revealed that the effects of Wnt5a are mediated by the Frizzled receptors and by the small GTPase, Rac1 (a component of the non-canonical Wnt planar cell polarity pathway). Moreover, the effects were specific as they could be blocked by Wnt5a antibody, sFRPs and RYK-Fc. The importance of Wnt5a in DA axon morphogenesis was further verified in Wnt5a (−/−) mice, where fasciculation of the medial forebrain bundle (MFB) as well as the density of DA neurites in the MFB and striatal terminals were disrupted. Thus, our results identify a novel role of Wnt5a in DA axon growth and guidance. Public Library of Science 2011-03-31 /pmc/articles/PMC3069098/ /pubmed/21483795 http://dx.doi.org/10.1371/journal.pone.0018373 Text en Blakely et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Blakely, Brette D. Bye, Christopher R. Fernando, Chathurini V. Horne, Malcolm K. Macheda, Maria L. Stacker, Steven A. Arenas, Ernest Parish, Clare L. Wnt5a Regulates Midbrain Dopaminergic Axon Growth and Guidance |
title | Wnt5a Regulates Midbrain Dopaminergic Axon Growth and
Guidance |
title_full | Wnt5a Regulates Midbrain Dopaminergic Axon Growth and
Guidance |
title_fullStr | Wnt5a Regulates Midbrain Dopaminergic Axon Growth and
Guidance |
title_full_unstemmed | Wnt5a Regulates Midbrain Dopaminergic Axon Growth and
Guidance |
title_short | Wnt5a Regulates Midbrain Dopaminergic Axon Growth and
Guidance |
title_sort | wnt5a regulates midbrain dopaminergic axon growth and
guidance |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3069098/ https://www.ncbi.nlm.nih.gov/pubmed/21483795 http://dx.doi.org/10.1371/journal.pone.0018373 |
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