Differential modulation of BMP signaling promotes the elaboration of cerebral cortical GABAergic neurons or oligodendrocytes from a common sonic hedgehog-responsive ventral forebrain progenitor species

Proc Natl Acad Sci U S A. 2002 Dec 10;99(25):16273-8. doi: 10.1073/pnas.232586699. Epub 2002 Dec 2.

Abstract

During cerebral cortical development, excitatory glutamatergic projection neurons are generated from neural stem cells intrinsic to the early embryonic cortical ventricular zone by a process of radial migration, whereas most inhibitory gamma-aminobutyric acid (GABA)ergic interneurons and oligodendrocytes (OLs) appear to be elaborated from ventral forebrain stem cells that initially undergo tangential cortical migration before terminal lineage maturation. In contrast to the more compartmentalized developmental organization of the spinal cord, the generation of neurons and OLs from a common ventral forebrain stem cell would expose these cells to the sequential actions of ventral and dorsal gradient morphogens [sonic hedgehog (Shh) and bone morphogenetic proteins (BMPs)] that normally mediate opposing developmental programs. Here we report that Shh promotes GABAergic neuronalOL lineage restriction of forebrain stem cells, in part, by activation of the basic helix-loop-helix transcription factors, Olig2 and Mash1. In mutant mice with a generalized defect in tangential cortical migration (Dlx12--), there is a profound and selective reduction in the elaboration of both cortical GABAergic neurons and OLs. Our studies further demonstrate that the sequential elaboration of cortical GABAergic neurons and OLs from common Shh-responsive ventral forebrain progenitors requires the spatial and temporal modulation of cortical BMP signaling by BMP ligands and the BMP antagonist, noggin, respectively. These findings suggest an integrative model for cerebral cortical GABAergic neuronal and OL lineage maturation that would incorporate the sequential contributions of the ventral and dorsal forebrain, and the potential role of regional developmental cues in modulating transcriptional codes within evolving neural lineage species.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors
  • Bone Morphogenetic Protein 2
  • Bone Morphogenetic Proteins / physiology*
  • Cell Lineage
  • Cells, Cultured / cytology
  • Cells, Cultured / drug effects
  • Cerebral Cortex / cytology*
  • DNA-Binding Proteins / physiology
  • Gene Expression Regulation, Developmental / drug effects
  • Genes, Homeobox
  • Genes, Reporter
  • Green Fluorescent Proteins
  • Hedgehog Proteins
  • Homeodomain Proteins / genetics
  • Luminescent Proteins / genetics
  • Mice
  • Mice, Knockout
  • Models, Neurological
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / physiology
  • Neurons / cytology*
  • Oligodendrocyte Transcription Factor 2
  • Oligodendroglia / cytology*
  • Oligodeoxyribonucleotides, Antisense / pharmacology
  • Prosencephalon / cytology*
  • Recombinant Fusion Proteins / physiology
  • Trans-Activators / physiology*
  • Transcription Factors / physiology
  • Transforming Growth Factor beta*
  • gamma-Aminobutyric Acid / analysis

Substances

  • Ascl1 protein, mouse
  • Basic Helix-Loop-Helix Transcription Factors
  • Bmp2 protein, mouse
  • Bone Morphogenetic Protein 2
  • Bone Morphogenetic Proteins
  • DNA-Binding Proteins
  • Distal-less homeobox proteins
  • Hedgehog Proteins
  • Homeodomain Proteins
  • Luminescent Proteins
  • Nerve Tissue Proteins
  • Olig2 protein, mouse
  • Oligodendrocyte Transcription Factor 2
  • Oligodeoxyribonucleotides, Antisense
  • Recombinant Fusion Proteins
  • SHH protein, human
  • Trans-Activators
  • Transcription Factors
  • Transforming Growth Factor beta
  • Green Fluorescent Proteins
  • gamma-Aminobutyric Acid