Rho GTPases regulate PTPμ-mediated nasal neurite outgrowth and temporal repulsion of retinal ganglion cell neurons

Abstract

Members of the receptor protein tyrosine phosphatase (RPTP) subfamily of cell adhesion molecules (CAMs) mediate neurite outgrowth and growth cone repulsion. PTPmu is a growth permissive substrate for nasal retinal ganglion cell (RGC) neurites and a growth inhibitory substrate for temporal RGCs. In this manuscript, we demonstrate that the distinct PTPmu-dependent phenotypes of nasal outgrowth and temporal repulsion are regulated by Rho GTPases. The role of Rho GTPases in the regulation of nasal outgrowth and temporal repulsion was tested by utilizing dominant negative and constitutively active forms of Rac1, RhoA and Cdc42 in Bonhoeffer stripe assays. Nasal neurite outgrowth on PTPmu was blocked by Cdc42-DN. Temporal repulsion to a PTPmu substrate was substantially reduced by addition of Cdc42-DN. The molecule that regulates the switch between permissive versus repulsive responses to PTPmu is Rac1 for temporal neurons. Inhibition of Rac1 is required for repulsion of temporal neurons. Interestingly, adding Rac1-CA to temporal RGC neurons converted PTPmu-dependent repulsion to a permissive response. In addition, adding exogenous Rac1-DN to nasal neurons induced a phenotype switch from a permissive to repulsive response to PTPmu. Together these data suggest that Cdc42 activity is required for both permissive and repulsive responses to PTPmu. However, the key to PTPmu-dependent repulsion is inhibition of Rac1 activity in temporal RGC neurons.

Are Molecules Involved in Neuritogenesis and Axon Guidance Related to Autism Pathogenesis?

“…RhoA is involved in growth cone retraction and plays a central role in inhibition of axon outgrowth by myelin-derived inhibitors (Thies andDavenport 2003, Auer et al 2012). Rac1 and Cdc42 regulate neurite outgrowth and the growth cone morphology of most neurons (Oblander andBradyKalnay 2010, Major andBrady-Kalnay 2007). Accumulating evidence indicates that another key mechanism by which Rac and Cdc42 relay signals to the actin cytoskeleton involves the Wiskott-Aldrich syndrome family of scaffolding proteins (Millard et al 2004;Smith andLi 2004, Govek et al 2005).…”

Distinct PTPmu-associated signaling molecules differentially regulate neurite outgrowth on E-, N-, and R-cadherin

“…Rac1 and Cdc42 regulate neurite outgrowth and growth cone morphology of most neurons including on a PTPμ substrate (Major and Brady-Kalnay, 2007). In order to test a role for the Rho GTPases in cadherin-mediated neurite outgrowth, E8 chick retinal explants were infected with HSV encoding GFP control (Fig.…”

“…Cdc42, Rac1 and RhoA are expressed in the chick retina and are involved in PTPμ-mediated growth cone rearrangement and neurite outgrowth (Major and Brady-Kalnay, 2007; Rosdahl et al, 2003). PTPμ promotes neurite outgrowth from nasal RGCs but is repulsive to temporal RGCs (Burden-Gulley et al, 2002).…”

“…Cdc42 activity is required for PTPμ-mediated nasal outgrowth and temporal repulsion. Temporal repulsion of these neurites also requires inhibition of Rac1 activity (Major and Brady-Kalnay, 2007). We have also previously shown that IQGAP1 binds directly to PTPμ and that the IQGAP1/PTPμ association increases in the presence of activated Cdc42 (Phillips-Mason et al, 2006), which is required for PTPμ-mediated neurite outgrowth (Phillips-Mason et al, 2006).…”

Regulation of development and cancer by the R2B subfamily of RPTPs and the implications of proteolysis

“…Tyrosine phosphatase activity of PTPμ is necessary for its regulation of neurite outgrowth [42]. Neurite outgrowth on a purified PTPμ substrate requires signaling via PLCγ1, PKCδ, the Rho GTPases Cdc42 and Rac1, and IQGAP1 [43–48]. …”