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Cover ArticleArticles, Development/Plasticity/Repair

Secreted Frizzled Related Proteins Modulate Pathfinding and Fasciculation of Mouse Retina Ganglion Cell Axons by Direct and Indirect Mechanisms

Séverine Marcos, Francisco Nieto-Lopez, Africa Sandonìs, Marcos Julian Cardozo, Fabiana Di Marco, Pilar Esteve and Paola Bovolenta
Journal of Neuroscience 18 March 2015, 35 (11) 4729-4740; DOI: https://doi.org/10.1523/JNEUROSCI.3304-13.2015
Séverine Marcos
1Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas–Universidad Autónoma de Madrid, Madrid 28049, Spain,
2Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid 28049, Spain, and
3Instituto Cajal, Consejo Superior de Investigaciones Científicas, 28002 Madrid, Spain
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Francisco Nieto-Lopez
1Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas–Universidad Autónoma de Madrid, Madrid 28049, Spain,
2Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid 28049, Spain, and
3Instituto Cajal, Consejo Superior de Investigaciones Científicas, 28002 Madrid, Spain
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Africa Sandonìs
1Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas–Universidad Autónoma de Madrid, Madrid 28049, Spain,
2Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid 28049, Spain, and
3Instituto Cajal, Consejo Superior de Investigaciones Científicas, 28002 Madrid, Spain
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Marcos Julian Cardozo
1Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas–Universidad Autónoma de Madrid, Madrid 28049, Spain,
2Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid 28049, Spain, and
3Instituto Cajal, Consejo Superior de Investigaciones Científicas, 28002 Madrid, Spain
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Fabiana Di Marco
1Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas–Universidad Autónoma de Madrid, Madrid 28049, Spain,
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Pilar Esteve
1Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas–Universidad Autónoma de Madrid, Madrid 28049, Spain,
2Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid 28049, Spain, and
3Instituto Cajal, Consejo Superior de Investigaciones Científicas, 28002 Madrid, Spain
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Paola Bovolenta
1Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas–Universidad Autónoma de Madrid, Madrid 28049, Spain,
2Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid 28049, Spain, and
3Instituto Cajal, Consejo Superior de Investigaciones Científicas, 28002 Madrid, Spain
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Abstract

Retina ganglion cell (RGC) axons grow along a stereotyped pathway undergoing coordinated rounds of fasciculation and defasciculation, which are critical to establishing proper eye–brain connections. How this coordination is achieved is poorly understood, but shedding of guidance cues by metalloproteinases is emerging as a relevant mechanism. Secreted Frizzled Related Proteins (Sfrps) are multifunctional proteins, which, among others, reorient RGC growth cones by regulating intracellular second messengers, and interact with Tolloid and ADAM metalloproteinases, thereby repressing their activity. Here, we show that the combination of these two functions well explain the axon guidance phenotype observed in Sfrp1 and Sfrp2 single and compound mouse mutant embryos, in which RGC axons make subtle but significant mistakes during their intraretinal growth and inappropriately defasciculate along their pathway. The distribution of Sfrp1 and Sfrp2 in the eye is consistent with the idea that Sfrp1/2 normally constrain axon growth into the fiber layer and the optic disc. Disheveled axon growth instead seems linked to Sfrp-mediated modulation of metalloproteinase activity. Indeed, retinal explants from embryos with different Sfrp-null alleles or explants overexpressing ADAM10 extend axons with a disheveled appearance, which is reverted by the addition of Sfrp1 or an ADAM10-specific inhibitor. This mode of growth is associated with an abnormal proteolytic processing of L1 and N-cadherin, two ADAM10 substrates previously implicated in axon guidance. We thus propose that Sfrps contribute to coordinate visual axon growth with a dual mechanism: by directly signaling at the growth cone and by regulating the processing of other relevant cues.

  • axon guidance
  • metalloproteinase
  • optic chiasm
  • optic disc
  • Sfrp
  • visual pathway
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The Journal of Neuroscience: 35 (11)
Journal of Neuroscience
Vol. 35, Issue 11
18 Mar 2015
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Secreted Frizzled Related Proteins Modulate Pathfinding and Fasciculation of Mouse Retina Ganglion Cell Axons by Direct and Indirect Mechanisms
Séverine Marcos, Francisco Nieto-Lopez, Africa Sandonìs, Marcos Julian Cardozo, Fabiana Di Marco, Pilar Esteve, Paola Bovolenta
Journal of Neuroscience 18 March 2015, 35 (11) 4729-4740; DOI: 10.1523/JNEUROSCI.3304-13.2015

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Secreted Frizzled Related Proteins Modulate Pathfinding and Fasciculation of Mouse Retina Ganglion Cell Axons by Direct and Indirect Mechanisms
Séverine Marcos, Francisco Nieto-Lopez, Africa Sandonìs, Marcos Julian Cardozo, Fabiana Di Marco, Pilar Esteve, Paola Bovolenta
Journal of Neuroscience 18 March 2015, 35 (11) 4729-4740; DOI: 10.1523/JNEUROSCI.3304-13.2015
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Keywords

  • axon guidance
  • metalloproteinase
  • optic chiasm
  • optic disc
  • Sfrp
  • visual pathway

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