PT  - JOURNAL ARTICLE
AU  - Séverine Marcos
AU  - Francisco Nieto-Lopez
AU  - Africa Sandonìs
AU  - Marcos Julian Cardozo
AU  - Fabiana Di Marco
AU  - Pilar Esteve
AU  - Paola Bovolenta
TI  - Secreted Frizzled Related Proteins Modulate Pathfinding and Fasciculation of Mouse Retina Ganglion Cell Axons by Direct and Indirect Mechanisms
AID  - 10.1523/JNEUROSCI.3304-13.2015
DP  - 2015 Mar 18
TA  - The Journal of Neuroscience
PG  - 4729--4740
VI  - 35
IP  - 11
4099  - http://www.jneurosci.org/content/35/11/4729.short
4100  - http://www.jneurosci.org/content/35/11/4729.full
SO  - J. Neurosci.2015 Mar 18; 35
AB  - 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.