Integration of left-right Pitx2 transcription and Wnt signaling drives asymmetric gut morphogenesis via Daam2

Dev Cell. 2013 Sep 30;26(6):629-44. doi: 10.1016/j.devcel.2013.07.019.

Abstract

A critical aspect of gut morphogenesis is initiation of a leftward tilt, and failure to do so leads to gut malrotation and volvulus. The direction of tilt is specified by asymmetric cell behaviors within the dorsal mesentery (DM), which suspends the gut tube, and is downstream of Pitx2, the key transcription factor responsible for the transfer of left-right (L-R) information from early gastrulation to morphogenesis. Although Pitx2 is a master regulator of L-R organ development, its cellular targets that drive asymmetric morphogenesis are not known. Using laser microdissection and targeted gene misexpression in the chicken DM, we show that Pitx2-specific effectors mediate Wnt signaling to activate the formin Daam2, a key Wnt effector and itself a Pitx2 target, linking actin dynamics to cadherin-based junctions to ultimately generate asymmetric cell behaviors. Our work highlights how integration of two conserved cascades may be the ultimate force through which Pitx2 sculpts L-R organs.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Animals
  • Cadherins / metabolism
  • Chick Embryo
  • Gastrulation*
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism*
  • Intestinal Mucosa / metabolism
  • Intestines / embryology*
  • Mesentery / embryology
  • Mesentery / metabolism
  • Mesoderm / metabolism
  • Mice
  • Microfilament Proteins / genetics
  • Microfilament Proteins / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcription, Genetic*
  • Wnt Signaling Pathway*
  • rho GTP-Binding Proteins / genetics
  • rho GTP-Binding Proteins / metabolism*

Substances

  • Actins
  • Cadherins
  • Daam2 protein, mouse
  • Homeodomain Proteins
  • Microfilament Proteins
  • Transcription Factors
  • homeobox protein PITX2
  • rho GTP-Binding Proteins