Conserved regulation of Nodal-mediated left-right patterning in zebrafish and mouse

Abstract

Nodal is the major effector of left-right axis development. In mice, Nodal forms heterodimers with Gdf1 and is inhibited by Cerl2/Dand5 at the node, and by Lefty1 in the lateral plate mesoderm (LPM). Studies in zebrafish have suggested some parallels, but also differences, between left-right patterning in mouse and zebrafish. To address these discrepancies, we generated single and double zebrafish mutants for southpaw (spaw, the Nodal ortholog), dand5 and lefty1, and performed biochemical and activity assays with Spaw and Vg1/ Gdf3 (the Gdf1 ortholog). Contrary to previous findings, spaw mutants failed to initiate spaw expression in the LPM, and asymmetric heart looping was absent, similar to mouse Nodal mutants. In blastoderm assays, Vg1 and Spaw were interdependent for target gene induction, and contrary to previous results, formed heterodimers. Loss of Dand5 or Lefty1 caused bilateral spaw expression, similar to mouse mutants, and Lefty1 was replaceable with a uniform Nodal signaling inhibitor. Collectively, these results indicate that Dand5 activity biases Spaw-Vg1 heterodimer activity to the left, Spaw around Kupffer's vesicle induces the expression of spaw in the LPM and global Nodal inhibition maintains the left bias of Spaw activity, demonstrating conservation between zebrafish and mouse mechanisms of left-right patterning.

Pinhead antagonizes Admp to promote notochord formation

“…1D). Among these were Nodal inhibitors, Dand5/Coco/Cerl2 and Lefty/Antivin (Bell et al, 2003;Cheng et al, 2000;Marques et al, 2004;Meno et al, 1998;Montague et al, 2018), and Pnhd itself, consistent with the reported ability of Pnhd to form dimers (Yan et al, 2019). A top candidate (32 identified peptides) corresponded to Admp, a BMP family protein that is expressed in the Spemann organizer and involved in dorsoventral patterning (Moos et al, 1995;Reversade and De Robertis, 2005).…”

Evolutionary Changes in Left-Right Visceral Asymmetry inAstyanaxCavefish

“…Bilaterally symmetric animals generally show superficial symmetry of external structures but distinct asymmetries in many internal organs. During vertebrate development visceral organs such as the heart and gut tubes bend asymmetrically and develop at predetermined positions favoring the left or right side of the midline [1][2][3][4].…”

“…

Vertebrates show conserved left-right (L-R) asymmetry of internal organs controlled by Nodal-Pitx2/Lefty signaling [1][2][3]. Modifications in L-R asymmetry occur in mutants [4] and rarely in humans [5], but little is known about natural L-R changes during evolution. Here we describe changes in L-R asymmetry in Astyanax mexicanus, a teleost with ancestral surface (surface fish) and derived cave (cavefish) morphs [6].

…”

Molecular mechanisms controlling the biogenesis of the TGF-β signal Vg1

“…The TGF-beta signals Nodal and Vg1 (Dvr1/Gdf3) play crucial roles in vertebrate development (Schier 2009; Rogers and Muller 2019), including the induction of mesendoderm and the generation of left-right asymmetry (Dale, Matthews, and Colman 1993; Thomsen and Melton 1993; Zhou et al 1993; Conlon et al 1994; Feldman et al 1998; Birsoy et al 2006; Bisgrove, Su, and Yost 2017; Montague and Schier 2017; Pelliccia, Jindal, and Burdine 2017; Levin et al 1995; Collignon, Varlet, and Robertson 1996; Lowe et al 1996; Pagan-Westphal and Tabin 1998; Long, Ahmad, and Rebagliati 2003; Montague, Gagnon, and Schier 2018). For example in zebrafish, secreted Vg1-Nodal heterodimers induce a gradient of signaling that patterns the embryonic mesendoderm (Montague and Schier 2017).…”