Autonomic neurogenesis and apoptosis are alternative fates of progenitor cell communities induced by TGFbeta

Dev Biol. 2000 Dec 1;228(1):57-72. doi: 10.1006/dbio.2000.9936.

Abstract

The question of how appropriate cell types are generated in correct numbers during development of the peripheral nervous system has become particularly intriguing with the identification of multipotent progenitor cells in postmigratory targets of the neural crest. Recently, we have provided evidence that community effects in response to factors of the TGFbeta family might represent a mechanism to suppress inappropriate nonneural fates from multipotent progenitors in developing peripheral ganglia. In culture, BMP2 and TGFbeta promote neurogenesis at the expense of a smooth-muscle-like fate in clusters of neural-crest-derived multipotent progenitor cells. We now show that the neurons generated by TGFbeta factors belong to the autonomic lineage and that cells within the developing sympathetic ganglia express TGFbeta-type II receptor. In addition to its neurogenic activity, TGFbeta but not BMP2 also induces apoptosis as an alternative fate in cultured progenitor communities. Interestingly, these fate decisions are controlled by graded changes in TGFbeta concentrations: lower doses of TGFbeta promote neurogenesis while slightly higher doses induce predominantly apoptosis. These effects of TGFbeta are specific for an early developmental stage since progenitor cells lose their competence to respond to the proapoptotic activity of TGFbeta upon neuronal differentiation. In vivo, the expression of TGFbeta3 in differentiated neurons suggests that the signal concentration gradually increases with the number of neurons formed in the autonomic ganglia. We propose that TGFbeta functions in a biphasic manner during autonomic gangliogenesis to control both neurogenesis and subsequently the number of neurons generated from progenitor cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Autonomic Nervous System / cytology
  • Autonomic Nervous System / drug effects*
  • Autonomic Nervous System / embryology
  • Basic Helix-Loop-Helix Transcription Factors
  • Bone Morphogenetic Protein 2
  • Bone Morphogenetic Proteins / pharmacology
  • Cell Aggregation
  • Cell Count
  • Cell Differentiation / drug effects
  • Cell Division / drug effects
  • Cells, Cultured
  • DNA-Binding Proteins / metabolism
  • Dose-Response Relationship, Drug
  • Ganglia, Autonomic / cytology
  • Ganglia, Autonomic / drug effects
  • Ganglia, Autonomic / embryology
  • Immunohistochemistry
  • In Situ Nick-End Labeling
  • Neural Crest / cytology
  • Neural Crest / drug effects*
  • Neural Crest / embryology
  • Neurons / cytology
  • Neurons / drug effects*
  • Protein Isoforms / biosynthesis
  • Protein-Serine-Threonine Kinases
  • Rats
  • Rats, Inbred Strains
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / metabolism
  • Stem Cells / cytology
  • Stem Cells / drug effects*
  • Transcription Factors / metabolism
  • Transforming Growth Factor beta / biosynthesis
  • Transforming Growth Factor beta / pharmacology*

Substances

  • Ascl1 protein, rat
  • Basic Helix-Loop-Helix Transcription Factors
  • Bmp2 protein, rat
  • Bone Morphogenetic Protein 2
  • Bone Morphogenetic Proteins
  • DNA-Binding Proteins
  • Protein Isoforms
  • Receptors, Transforming Growth Factor beta
  • Transcription Factors
  • Transforming Growth Factor beta
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II