Secreted frizzled related proteins modulate pathfinding and fasciculation of mouse retina ganglion cell axons by direct and indirect mechanisms

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 whichRGCaxons 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.Wethus 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 cuesThis work was supported by the Spanish MINECO (Grants BFU2010-16031 and BFU2013-43213-P), Comunidad Autónoma de Madrid (Grant S2010/BMD-2315) Cost Action BM1001 Brain ECM in Health and Disease, an institutional grant from the Fundación Ramón Areces and Centro de Investigación Biomédica en Red de Enfermedades Raras (P.B.). F.N.-L. and M.J.C. were supported by a FPU and FPI fellowship from the Spanish Government, respectively. We thank F. Murakami, L. Erskine, A. Chedotal, A. Ludwig, and V.P. Lemmon for reagent

SFRPs act as negative modulators of ADAM10 to regulate retinal neurogenesis

10.1038/nn.2794Nature Neuroscience145562-570NANE