BMP and retinoic acid regulate anterior–posterior patterning of the non-axial mesoderm across the dorsal–ventral axis

Abstract

Despite the fundamental importance of patterning along the dorsal–ventral (DV) and anterior–posterior (AP) axes during embryogenesis, uncertainty exists in the orientation of these axes for the mesoderm. Here we examine the origin and formation of the zebrafish kidney, a ventrolateral mesoderm derivative, and show that AP patterning of the non-axial mesoderm occurs across the classic gastrula stage DV axis while DV patterning aligns along the animal–vegetal pole. We find that BMP signalling acts early to establish broad anterior and posterior territories in the non-axial mesoderm while retinoic acid (RA) functions later, but also across the classic DV axis. Our data support a model in which RA on the dorsal side of the embryo induces anterior kidney fates while posterior kidney progenitors are protected ventrally by the RA-catabolizing enzyme Cyp26a1. This work clarifies our understanding of vertebrate axis orientation and establishes a new paradigm for how the kidney and other mesodermal derivatives arise during embryogenesis.

RARγ is required for mesodermal gene expression prior to gastrulation in Xenopus

“…RA, in combination with BMP4, can induce the production of mesodermal precursors from embryonic stem cells (Torres et al, 2012), and many mesodermal derivatives (e.g. somites, heart, kidney, gonads) are affected when RA signaling is perturbed (Cartry et al, 2006;Hasegawa and Saga, 2012;Rhinn and Dolle, 2012, and reviewed by Cunningham and Duester, 2015;Naylor et al, 2016). Here, we propose a new role for RARγ signaling and show that it is required much earlier than had been previously thought for the expression of mesodermal markers, in vivo.…”

“…RAR signaling is implicated in numerous developmental processes, including patterning and boundary-setting, proliferation/ differentiation and organogenesis (Niederreither et al, 2001;Maden, 2007;Rhinn and Dolle, 2012;Janesick et al, 2013;Cunningham and Duester, 2015). RA is essential for the development of many non-axial mesodermal derivatives, in particular the heart, somites and kidney (Niederreither et al, 2001;Moreno and Kintner, 2004;Naylor et al, 2016). We previously showed that liganded RARβ2 in the trunk is required for somite patterning and number, hypaxial muscle migration, and restriction of the presomitic mesoderm, whereas unliganded RARγ maintains the size of the presomitic mesoderm and the pool of bipotential caudal progenitor cells (Janesick et al, 2014(Janesick et al, , 2017.…”

Regulating Retinoic Acid Availability during Development and Regeneration: The Role of the CYP26 Enzymes

“…In the developing zebrafish kidney, a similar mechanism specifies the dorsoventral axis. RA on the dorsal side of the embryo specifies anterior kidney fates, whereas expression of cyp26a1 ventrally is necessary to inhibit RA signalling allowing the induction of ventral kidney progenitors [356]. Moreover, the cdx1a and cdx4 regulate the posterior boundaries of expression of raldh2 and cyp26a1 in the anterior paraxial mesoderm to correctly position the zebrafish pronephros along the anterior-posterior axis [357].…”

Inhibition of GSK3 Represses the Expression of Retinoic Acid Synthetic Enzyme ALDH1A2 via Wnt/β-Catenin Signaling in WiT49 Cells

“…In zebrafish pronephros, cdx mutation leads to Aldh1a2 upregulation and disrupts pronephros positioning and distal segment formation (Wingert et al, 2007), suggesting that inhibition of Aldh1a2 expression by cdx is critical for pronephros development. Recently, it was shown that anterior kidney fates are induced by retinoic acid on the dorsal side of the embryo with Aldh1a2 expression, while posterior kidney progenitors are protected by the Cyp26a1 enzyme (Naylor et al, 2016). These studies suggest that Aldh1a2 expression determines the precise localization of retinoic acid signaling and that the repression of the Aldh1a2 is necessary for the pronephros formation of zebrafish.…”