Telencephalon-specific Rb knockouts reveal enhanced neurogenesis, survival and abnormal cortical development

EMBO J. 2002 Jul 1;21(13):3337-46. doi: 10.1093/emboj/cdf338.

Abstract

Correct cell cycle regulation and terminal mitosis are critical for nervous system development. The retinoblastoma (Rb) protein is a key regulator of these processes, as Rb-/- embryos die by E15.5, exhibiting gross hematopoietic and neurological defects. The extensive apoptosis in Rb-/- embryos has been attributed to aberrant S phase entry resulting in conflicting growth control signals in differentiating cells. To assess the role of Rb in cortical development in the absence of other embryonic defects, we examined mice with telencephalon-specific Rb deletions. Animals carrying a floxed Rb allele were interbred with mice in which cre was knocked into the Foxg1 locus. Unlike germline knockouts, mice specifically deleted for Rb in the developing telencephalon survived until birth. In these mutants, Rb-/- progenitor cells divided ectopically, but were able to survive and differentiate. Mutant brains exhibited enhanced cellularity due to increased proliferation of neuroblasts. These studies demonstrate that: (i) cell cycle deregulation during differentiation does not necessitate apoptosis; (ii) Rb-deficient mutants exhibit enhanced neuroblast proliferation; and (iii) terminal mitosis may not be required to initiate differentiation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Animals
  • Apoptosis
  • Biomarkers
  • Cell Cycle
  • Cell Differentiation
  • Cell Division
  • Cerebral Cortex / abnormalities
  • Cerebral Cortex / embryology
  • Crosses, Genetic
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics
  • Fetal Death / genetics
  • Forkhead Transcription Factors
  • Genes, Lethal
  • Genes, Retinoblastoma
  • Mice
  • Mice, Knockout
  • Mutagenesis, Insertional
  • Nerve Tissue Proteins / deficiency
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / physiology*
  • Neurons / pathology
  • Organ Specificity
  • Retinoblastoma Protein / deficiency
  • Retinoblastoma Protein / physiology*
  • Telencephalon / abnormalities
  • Telencephalon / embryology*
  • Tubulin / biosynthesis
  • Tubulin / genetics

Substances

  • Biomarkers
  • DNA-Binding Proteins
  • Forkhead Transcription Factors
  • Foxd1 protein, mouse
  • Nerve Tissue Proteins
  • Retinoblastoma Protein
  • Tubulin
  • beta3 tubulin, mouse