title: Secreted frizzled related proteins modulate pathfinding and fasciculation of mouse retina ganglion cell axons by direct and indirect mechanisms.
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.
authors: Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid 28049, Spain, Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid 28049, Spain, and Instituto Cajal, Consejo Superior de Investigaciones Científicas, 28002 Madrid, Spain.
authors: Séverine
authors: S
authors: Marcos
authors: Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid 28049, Spain, Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid 28049, Spain, and Instituto Cajal, Consejo Superior de Investigaciones Científicas, 28002 Madrid, Spain.
authors: Francisco
authors: F
authors: Nieto-Lopez
authors: Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid 28049, Spain, Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid 28049, Spain, and Instituto Cajal, Consejo Superior de Investigaciones Científicas, 28002 Madrid, Spain.
authors: Africa
authors: A
authors: Sandonìs
authors: Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid 28049, Spain, Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid 28049, Spain, and Instituto Cajal, Consejo Superior de Investigaciones Científicas, 28002 Madrid, Spain.
authors: Marcos Julian
authors: MJ
authors: Cardozo
authors: Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid 28049, Spain.
authors: Fabiana
authors: F
authors: Di Marco
authors: Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid 28049, Spain, Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid 28049, Spain, and Instituto Cajal, Consejo Superior de Investigaciones Científicas, 28002 Madrid, Spain.
authors: Pilar
authors: P
authors: Esteve
authors: Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid 28049, Spain, Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid 28049, Spain, and Instituto Cajal, Consejo Superior de Investigaciones Científicas, 28002 Madrid, Spain pbovolenta@cbm.csic.es.
authors: Paola
authors: P
authors: Bovolenta
mesh_terms: D000818:Animals; D001369:Axons / Q000502:physiology*; D005260:Female; D051157:Frizzled Receptors / Q000502:physiology; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D008297:Male; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012165:Retinal Ganglion Cells / Q000502:physiology*; D014795:Visual Pathways / Q000196:embryology* / Q000254:growth & development*; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D051157:Frizzled Receptors; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C485539:Sfrp1 protein, mouse; D000094742:Secreted Frizzled-Related Proteins; C491628:Sfrp2 protein, mouse
keywords: Sfrp; axon guidance; metalloproteinase; optic chiasm; optic disc; visual pathway