Drivers of Vessel Progenitor Fate Define Intermediate Mesoderm Dimensions by Inhibiting Kidney Progenitor Specification

Abstract

Proper organ formation depends on the precise delineation of organ territories containing defined numbers of progenitor cells. Kidney progenitors reside in bilateral stripes of posterior mesoderm that are referred to as the intermediate mesoderm (IM). Previously, we showed that the transcription factors Hand2 and Osr1 act to strike a balance between the specification of the kidney progenitors in the IM and the vessel progenitors in the laterally adjacent territory. Recently, the transcription factor Npas4l – an early and essential driver of vessel and blood progenitor formation – was shown to inhibit kidney development. Here we demonstrate how kidney progenitor specification is coordinated byhand2,osr1, andnpas4l. We find thatnpas4lis necessary to inhibit IM formation. Consistent with the expression ofnpas4lflanking the medial and lateral sides of the IM, our findings suggest roles fornpas4lin defining the IM boundaries at each of these borders. At the lateral IM border,hand2promotes andosr1inhibits the formation ofnpas4l-expressing lateral vessel progenitors, andhand2requiresnpas4lto inhibit IM formation and to promote vessel formation. Meanwhile,npas4lappears to have an additional role in suppressing IM fate at the medial border:npas4lloss-of-function enhanceshand2mutant IM defects and results in excess IM generated outside of the lateralhand2-expressing territory. Together, our findings reveal that establishment of the medial and lateral boundaries of the IM requires inhibition of kidney progenitor specification by the neighboring drivers of vessel progenitor fate.