Nodal Signaling Range Is Regulated by Proprotein Convertase-Mediated Maturation

Abstract

Tissue patterning is established by extracellular growth factors or morphogens. Although different theoretical models explaining specific patterns have been proposed, our understanding of tissue pattern establishment in vivo remains limited. In many animal species, left-right patterning is governed by a reaction-diffusion system relying on the different diffusivity of an activator, Nodal, and an inhibitor, Lefty. In a genetic screen, we identified a zebrafish loss-of-function mutant for the proprotein convertase FurinA. Embryological and biochemical experiments demonstrate that cleavage of the Nodal-related Spaw proprotein into a mature form by FurinA is required for Spaw gradient formation and activation of Nodal signaling. We demonstrate that FurinA is required cell-autonomously for the long-range signaling activity of Spaw and no other Nodal-related factors. Combined in silico and in vivo approaches support a model in which FurinA controls the signaling range of Spaw by cleaving its proprotein into a mature, extracellular form, consequently regulating left-right patterning.

Diversification of metazoan Kexin-like proprotein convertases: insights from the leechHelobdella

“…Although we had not succeeded in verifying the cleavage of Hau-BMP5-8 in the germinal band, we nevertheless demonstrated that such cleavage is irrelevant to Hau-BMP5-8's ability to induce the P fate. This finding is in stark contrast to the situation in vertebrate embryos, in which overexpression of BMP4 or BMP7 with mutated cleavage sites has a dominant-negative effect (Hawley, et al 1995); on the other hand the apparent irrelevance of convertase-mediated cleavage in the leech germinal band resembles the convertase-resistant mutant of the zebrafish nodal homolog Southpaw, which exhibits a similarly short-range signal activity, rather than a complete loss of signal (Tessadori, et al 2015). The endogenous Hau-BMP5-8 may likewise be in a prodomain-bound form, regardless of whether it is proteolytically processed or not, and the presence of the prodomain may restrict the signaling range of BMP5-8, without interfering with its receptor binding.…”

Extracellular interactions and ligand degradation shape the nodal morphogen gradient

“…The Nodal precursors are cleaved by extracellular convertases, and convertase processing was found to be essential for Nodal activation in zebrafish and mouse embryonic tissues ( Beck et al, 2002 ; Le Good et al, 2005 ). A recent report found that FurinA convertase activity regulates long range signaling by the zebrafish left-right patterning Nodal, Southpaw (Spaw), but not other Nodal factors ( Tessadori et al, 2015 ). Upon activation, Nodal proteins form complexes with type II and type I Activin receptors (Acvr1b; Acvr2a/b), which are serine/threonine kinases ( Reissmann et al, 2001 ; Yan et al, 2002 ; Yeo and Whitman, 2001 ) and activate the Nodal pathway ( Jia et al, 2008 ; Kumar, 2000 ; Massagué et al, 2005 ; Whitman, 1998 ).…”

A novel TRIM family member, Trim69, regulates zebrafish development through p53‐mediated apoptosis

“…Danio rerio (zebrafish) has become a favored model organism for studying biological processes due to their short period of reproduction, high reproduction rates, transparent embryos, and their ability to perform oviposition and fertilization in vitro (Bonora et al, 2015;Ding et al, 2015;Haesemeyer and Schier, 2015;Nishimura et al, 2015;Preston and Macklin, 2015;Wang et al, 2015). These unique properties make zebrafish particularly useful for studying embryogenesis, neurogenesis, hematopoiesis, organogenesis, and organ regeneration (Barriga et al, 2015;Navis and Bagnat, 2015;Panza et al, 2015;Tessadori et al, 2015).…”