Pleiotropic and isoform-specific functions for Pitx2 in superior colliculus and hypothalamic neuronal development

Mol Cell Neurosci. 2013 Jan;52:128-39. doi: 10.1016/j.mcn.2012.11.007. Epub 2012 Nov 10.

Abstract

Transcriptional regulation of gene expression during development is critical for proper neuronal differentiation and migration. Alternative splicing and differential isoform expression have been demonstrated for most mammalian genes, but their specific contributions to gene function are not well understood. In mice, the transcription factor gene Pitx2 is expressed as three different isoforms (PITX2A, PITX2B, and PITX2C) which have unique amino termini and common DNA binding homeodomains and carboxyl termini. The specific roles of these isoforms in neuronal development are not known. Here we report the onset of Pitx2ab and Pitx2c isoform-specific expression by E9.5 in the developing mouse brain. Using isoform-specific Pitx2 deletion mouse strains, we show that collicular neuron migration requires PITX2AB and that collicular GABAergic differentiation and targeting of hypothalamic projections require unique Pitx2 isoform dosage. These results provide insights into Pitx2 dosage and isoform-specific requirements underlying midbrain and hypothalamic development.

Publication types

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

MeSH terms

  • Animals
  • Cell Differentiation / physiology
  • Cell Movement / physiology
  • Fluorescent Antibody Technique
  • Gene Expression Regulation, Developmental
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism*
  • Hypothalamus / embryology*
  • Hypothalamus / metabolism
  • Immunohistochemistry
  • In Situ Hybridization
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microscopy, Confocal
  • Neurogenesis / physiology*
  • Neurons / cytology
  • Neurons / metabolism*
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Real-Time Polymerase Chain Reaction
  • Superior Colliculi / embryology*
  • Superior Colliculi / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*

Substances

  • Homeodomain Proteins
  • Protein Isoforms
  • Transcription Factors
  • homeobox protein PITX2