Interplay between activin and Hox genes determines the formation of the kidney morphogenetic field

Abstract

The kidney develops in a specific position along the anterior-posterior axis. All vertebrate kidney tissues are derived from the intermediate mesoderm (IM), and early kidney genes such as Lim1 and Pax2 are expressed in amniotes posterior to the sixth somite axial level. IM cells anterior to this level do not express kidney genes owing to changes in their competence to respond to kidneyinductive signals present along the entire axis. We aimed to understand the molecular mechanisms governing the loss of competence of anterior IM cells and the formation of the anterior border of the kidney morphogenetic field. We identified the dorsal neural tube as the potential kidney-inductive tissue and showed that activin, a secreted morphogen, is necessary but insufficient for Lim1 induction and establishment of the kidney field. Activin or activin-like and BMP signaling cascades are activated along the entire axis, including in anterior non-kidney IM, suggesting that competence to respond to these signals involves downstream or other components. Detailed expression pattern analysis of Hox genes during early chick development revealed that paralogous group four genes share the same anterior border as the kidney genes. Ectopic expression of Hoxb4 in anterior non-kidney IM, either by retinoic acid (RA) administration or plasmid-mediated overexpression, resulted in ectopic kidney gene expression. The anterior expansion of Lim1 expression was restrained when Hoxb4 was co-expressed with a truncated form of activin receptor. We suggest a model in which the competence of IM cells to respond to TGFβ signaling and express kidney genes is driven by RA and mediated by Hoxb4.

Comparative spatiotemporal analysis of Hox gene expression in early stages of intermediate mesoderm formation

“…Although the focus and theme of this article is Hox gene expression in early stages of kidney field specification, we also describe the kinetics of the expression of these genes in other mesodermal tissues. This is particularly important as several previous studies, including studies from our lab, show the crucial effect of neighboring tissues on IM specification at early developmental stages and the establishment of the kidney morphogenetic field (Mauch et al, 2000;Obara-Ishihara et al, 1999; and Schultheiss, 2003Barak et al, 2005;Preger-Ben Noon et al, 2009).…”

“…Preger-Ben Noon et al (2009) have demonstrated the role played by Hoxb4 in conferring the competence of IM cells to respond to activin-like signals emanating along the entire axis (including non-kidney IM) from the dorsal neural tube to induce early kidney genes. Because this gene exhibits an anterior expression boundary at the sixth somite level, it was suggested that the lack of Hoxb4 in anterior IM tissue attributes to the loss of kidney gene expression in this region despite the presence of kidneyinductive signals (Barak et al, 2005;Preger-Ben Noon et al, 2009). If this is correct, then the position of the pronephros along the IM A-P axis can be considered to be Hoxb4-dependent.…”

“…While still in the PS, the prospective IM has the potential to develop into a kidney fate but requires extrinsic signals to become specify (a degree of the determination state; Slack, 1983;Barak et al, 2005). These signals, including Activin/nodal like factors, are emanating from the dorsal neural tube along the entire axis including anterior non-kidney generating IM (Barak et al, 2005;Preger-Ben Noon et al, 2009). Moreover, HH stage 4 PS cells that fate anterior non-kidney IM are competent to respond to these signals and express the kidney markers, Pax2 and Lim1, if they are bridged over their migratory pathway and are transplanted directly into the anterior non-kidney IM.…”

“…(Barak et al, 2005). A recent study has shown the role that Hoxb4 is playing in conferring the competence of IM cells to respond to kidney-inductive signals and specify them into becoming pronephric tissue (Preger-Ben Noon et al, 2009).…”

“…In this study, we examined in detail the expression pattern of 10 Hox genes in the IM during early chick development with respect to the establishment of the anterior border of the kidney morphogenetic field and pronephros formation. This was done in light of the role played by Hoxb4 in conferring the competence of IM cells to respond to kidney-inductive signals (Preger-Ben Noon et al, 2009). Although the focus and theme of this article is Hox gene expression in early stages of kidney field specification, we also describe the kinetics of the expression of these genes in other mesodermal tissues.…”