Isl1 Is Upstream of Sonic Hedgehog in a Pathway Required for Cardiac Morphogenesis

Dev Biol. 2006 Jul 15;295(2):756-63. doi: 10.1016/j.ydbio.2006.03.053. Epub 2006 Apr 7.

Abstract

The LIM homeodomain transcription factor Islet1 (Isl1) is expressed in both foregut endoderm and cardiogenic mesoderm and is required for earliest stages of heart development. Here, we report that isl1 is also required upstream of Shh. We find that, in isl1 null mice, Sonic hedgehog (Shh) is downregulated in foregut endoderm. Shh signals through the unique activating receptor smoothened (Smo). To investigate the role of hedgehog signaling in the isl1 domain, we ablated smo utilizing isl1-cre. Isl1-cre;smo mutants exhibit cardiovascular defects similar to those observed in Shh null mice, defining a spatial requirement for hedgehog signaling within isl1 expression domains for aortic arch and outflow tract formation. Semaphorin signaling through neuropilin receptors npn1 and npn2 is required for aortic arch and outflow tract formation. We find that expression of npn2 is downregulated in isl1-cre;smo mutants, suggesting an isl1/Shh/npn pathway required to affect morphogenesis at the anterior pole of the heart.

Publication types

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

MeSH terms

  • Animals
  • Aorta, Thoracic
  • Cardiovascular Abnormalities / etiology
  • Heart / embryology*
  • Hedgehog Proteins
  • Homeodomain Proteins / metabolism*
  • Homeodomain Proteins / physiology
  • LIM-Homeodomain Proteins
  • Mice
  • Mice, Knockout
  • Morphogenesis*
  • Nerve Tissue Proteins / deficiency
  • Nerve Tissue Proteins / metabolism*
  • Nerve Tissue Proteins / physiology
  • Neuropilin-1 / metabolism*
  • Neuropilin-2
  • Neuropilins
  • Receptors, G-Protein-Coupled
  • Semaphorins
  • Smoothened Receptor
  • Trans-Activators / metabolism*
  • Trans-Activators / physiology
  • Transcription Factors

Substances

  • Hedgehog Proteins
  • Homeodomain Proteins
  • LIM-Homeodomain Proteins
  • Nerve Tissue Proteins
  • Neuropilin-2
  • Neuropilins
  • Receptors, G-Protein-Coupled
  • Semaphorins
  • Shh protein, mouse
  • Smo protein, mouse
  • Smoothened Receptor
  • Trans-Activators
  • Transcription Factors
  • insulin gene enhancer binding protein Isl-1
  • Neuropilin-1