Telencephalon-specific Rb knockouts reveal enhanced neurogenesis, survival and abnormal cortical development.
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.
Ferguson
Kerry L
KL
Ottawa Health Research Institute, University of Ottawa, 451 Smyth Road, Ottawa, ON, Canada K1H 8M5.
Vanderluit
Jacqueline L
JL
Hébert
Jean M
JM
McIntosh
W C
WC
Tibbo
Emma
E
MacLaurin
Jason G
JG
Park
David S
DS
Wallace
Valerie A
VA
Vooijs
Marc
M
McConnell
Susan K
SK
Slack
Ruth S
RS
D000483:Alleles; D000818:Animals; D017209:Apoptosis; D015415:Biomarkers; D002453:Cell Cycle; D002454:Cell Differentiation; D002455:Cell Division; D002540:Cerebral Cortex / Q000002:abnormalities / Q000196:embryology; D003433:Crosses, Genetic; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D005313:Fetal Death / Q000235:genetics; D051858:Forkhead Transcription Factors; D005804:Genes, Lethal; D016161:Genes, Retinoblastoma; D051379:Mice; D018345:Mice, Knockout; D016254:Mutagenesis, Insertional; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000473:pathology; D009928:Organ Specificity; D016160:Retinoblastoma Protein / Q000172:deficiency / Q000502:physiology*; D013687:Telencephalon / Q000002:abnormalities / Q000196:embryology*; D014404:Tubulin / Q000096:biosynthesis / Q000235:genetics
D015415:Biomarkers; D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; C489562:Foxd1 protein, mouse; D009419:Nerve Tissue Proteins; D016160:Retinoblastoma Protein; D014404:Tubulin; C462941:beta3 tubulin, mouse