Pitx2c orchestrates embryonic axis extension via mesendodermal cell migration.

Michelle M Collins,Marine Charpentier,Patrick Blader,Hans-Martin Maischein,Didier Yr Stainier,Pascale Dufourcq

doi:10.7554/elife.34880

Abstract

Pitx2c, a homeodomain transcription factor, is classically known for its left-right patterning role. However, an early wave of pitx2 expression occurs at the onset of gastrulation in several species, indicating a possible earlier role that remains relatively unexplored. Here we show that in zebrafish, maternal-zygotic (MZ) pitx2c mutants exhibit a shortened body axis indicative of convergence and extension (CE) defects. Live imaging reveals that MZpitx2c mutants display less persistent mesendodermal migration during late stages of gastrulation. Transplant data indicate that Pitx2c functions cell non-autonomously to regulate this cell behavior by modulating cell shape and protrusive activity. Using transcriptomic analyses and candidate gene approaches, we identify transcriptional changes in components of the chemokine-ECM-integrin dependent mesendodermal migration network. Together, our results define pathways downstream of Pitx2c that are required during early embryogenesis and reveal novel functions for Pitx2c as a regulator of morphogenesis.

Highlights

The process of gastrulation reorganizes cells of the embryonic blastula into the three primary germ layers through a series of complex cell movements
We show that the loss of maternal and zygotic Pitx2c function leads to reduced axis extension
We observed that MZpitx2c mutant embryos exhibit defects in convergence and extension movements in their axial and lateral mesoderm, and that persistent, oriented endodermal migration is impaired at late gastrulation stages

Summary

Introduction

The process of gastrulation reorganizes cells of the embryonic blastula into the three primary germ layers through a series of complex cell movements. Morphogenetic movements shape the embryo during gastrulation, but are crucial for its patterning by causing the cells to be exposed to particular signaling cues leading them to acquire specific cell fates. One cue that is critical during gastrulation is Nodal signaling, which drives cells towards mesendodermal fates. Nodal signaling activates many targets including itself and its own inhibitors, such as Lefty, to ensure tight spatial and temporal control (reviewed by Shen, 2007; Schier, 2009). In the context of left-right patterning, Nodal activates the expression of the transcription factor gene pitx2c (Bisgrove et al, 1999; Essner et al, 2000).

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Conclusion