A Homolog of Subtilisin-Like Proprotein Convertase 7 Is Essential to Anterior Neural Development in Xenopus

Abstract

BackgroundSubtilisin-like Proprotein Convertase 7 (SPC7) is a member of the subtilisin/kexin family of pro-protein convertases. It cleaves many pro-proteins to release their active proteins, including members of the bone morphogenetic protein (BMP) family of signaling molecules. Other SPCs are known to be required during embryonic development but corresponding data regarding SPC7 have not been reported previously.Methodology/Principal FindingsWe demonstrated that Xenopus SPC7 (SPC7) was expressed predominantly in the developing brain and eye, throughout the neural plate initially, then more specifically in the lens and retina primordia as development progressed. Since no prior functional information has been reported for SPC7, we used gain- and loss-of-function experiments to investigate the possibility that it may also convey patterning or tissue specification information similarly to Furin, SPC4, and SPC6. Overexpression of SPC7 was without effect. In contrast, injection of SPC7 antisense morpholino oligonucleotides (MO) into a single blastomere at the 2- or 4-cell stage produced marked disruption of head structures; anophthalmia was salient. Bilateral injections suppressed head and eye formation completely. In parallel with suppression of eye and brain development by SPC7 knockdown, expression of early anterior neural markers (Sox2, Otx2, Rx2, and Pax6) and late eye-specific markers (β-Crystallin and Opsin), and of BMP target genes such as Tbx2 and Tbx3, was reduced or eliminated. Taken together, these findings suggest a critical role for SPC7–perhaps, at least in part, due to activation of one or more BMPs–in early patterning of the anterior neural plate and its derivatives.Conclusion/SignificanceSPC7 is required for normal development of the eye and brain, possibly through processing BMPs, though other potential substrates cannot be excluded.

The motif EXEXXXL in the cytosolic tail of the secretory human proprotein convertase PC7 regulates its trafficking and cleavage activity

“…Accordingly, we either overexpressed or silenced the subunit of either AP-1 or AP-2 in HeLa and HEK293 cells (Figs. [9][10][11][12].…”

The shape of the human language-ready brain

“…In particular, the interaction between BMP7 and OTX2 is important for the development of different brain regions: at least, the mid- and hindbrain ( Tilleman et al, 2010 ) and the neuroepithelium ( von Frowein et al, 2006 ; Müller et al, 2007 ). Moreover, the protease SPC7 cleaves the pro-BMP7 to release the corresponding active protein; in turn, SPC7 knockdown is claimed to reduce the expression of OTX2 in the anterior brain ( Senturker et al, 2012 ). Additionally, both DLX1 and OTX2 are regionally restricted brain genes, important for the first stages of brain development ( Yamamoto and Vernier, 2011 ).…”

PC7 and the related proteases Furin and Pace4 regulate E-cadherin function during blastocyst formation

“…Furin and Pace4 activate TGF-β signals mediated by Nodal to specify the fate of progenitor cells in the developing mouse epiblast ( Beck et al, 2002 ; Mesnard et al, 2011 ). In Xenopus laevis embryos, knockdown of PC7 suppresses eye development ( Senturker et al, 2012 ), and a PC7-like activity can cleave pro-BMP4 during gastrulation ( Nelsen and Christian, 2009 ). However, a role for PC7 in the mouse embryo is elusive.…”