Protocadherin PAPC is expressed in the CNC and can compensate for the loss of PCNS

Abstract

Protocadherins represent the biggest subgroup within the cadherin superfamily of transmembrane glycoproteins. In contrast to classical type I cadherins, protocadherins in general exhibit only moderate adhesive activity. During embryogenesis, they are involved in cell signaling and regulate diverse morphogenetic processes, including morphogenetic movements during gastrulation and neural crest migration. The two protocadherins paraxial protocadherin (PAPC) and axial protocadherin (AXPC) are indispensable for proper gastrulation movements in Xenopus and zebrafish. The closest relative PCNS instead, is required for neural crest and somite formation. Here, we show that cranial neural crest (CNC) cells in addition to PCNS express PAPC, but not AXPC. Overexpression of PAPC resulted in comparable migration defects as knockdown of PCNS. Moreover, reconstitution experiments revealed that PAPC is able to replace PCNS in CNC cells, indicating that both protocadherins can regulate CNC migration.

Ror2 signaling is required for local upregulation of GDF6 and activation of BMP signaling at the neural plate border

“…Papc coordinates convergent extension movements in the mesoderm (Medina et al, 2004;Schambony and Wedlich, 2007;Unterseher et al, 2004) and could thus contribute indirectly to neural morphogenesis. Notably, functional redundancy of Papc and Pcns has been reported in the context of neural crest migration (Schneider et al, 2014). Such redundancy most probably also accounts for the full rescue of neural cell polarity by Papc and the ability of both protocadherins to rescue NPB formation in Ror2-deficient embryos.…”

“…Interestingly, the known downstream target of Ror2, papc (Schambony and Wedlich, 2007), was also downregulated in Ror2-depleted DLMZ/ectoderm explants, which further supports a role for both protocadherin 8 orthologs downstream of Ror2 in NPB specification. Endogenously, however, additional functions of Ror2 must be assumed, because simultaneous depletion of both Pcns and Papc did not affect neural crest induction (Schneider et al, 2014).…”

“…PAPC acts as a modulator and co-factor of Wnt/PCP signaling that itself activates RhoA and Jnk signaling (Medina et al, 2004;Unterseher et al, 2004). Signaling activity of Pcns has not be characterized in detail, but a recent study showed that Papc can functionally substitute for Pcns in neural crest migration, indicating that both exhibit redundant signaling function (Schneider et al, 2014). When overexpressed, both proteins likely restore PCP signaling in the DLMZ and dorsal ectoderm irrespective of their endogenous expression, which impedes discrimination between functional compensation and true epistatic relationships.…”

“…In our previous work, we have demonstrated that Wnt5a/Ror2 signaling is essential for the upregulation of paraxial protocadherin (Papc) in gastrulating embryos and that Papc acts as a positive modulator of Wnt/PCP signaling (Schambony and Wedlich, 2007;Unterseher et al, 2004). Accordingly, we co-injected papc RNA or an RNA encoding the related and functionally redundant ectodermal protocadherin Pcns (Rangarajan et al, 2006;Schneider et al, 2014) to restore Wnt/PCP signaling in Ror2 morphant embryos. Indeed, expressing either Papc or Pcns was sufficient to rescue gdf6 expression in Ror2 deficient embryos (Fig.…”

The Wnt receptor Frizzled-4 modulates ADAM13 metalloprotease activity

“…It is, therefore, possible that the interaction of Fz with ADAM13 is important in order to protect PAPC from degradation during internalization. It should be noted that Wnt11, Fz4, Fz7, PAPC and ADAM13 are all expressed in the CNC cells during migration (Alfandari et al, 1997;De Calisto et al, 2005;Matthews et al, 2008;Schneider et al, 2014;Swain et al, 2005). Furthermore, ADAM13 is also regulated by one of the kinases GSK3 that control the Wnt pathway.…”