Cell cycle deregulation and loss of stem cell phenotype in the subventricular zone of TGF-β adaptor elf-/- mouse brain

Nady Golestaneh, Yi Tang, Varalakshmi Katuri, Wilma Jogunoori, Lopa Mishra, Bibhuti Mishra

Research output: Contribution to journalArticle

Abstract

The mammalian forebrain subependyma contains neural stem cells and other proliferating progenitor cells. Recent studies have shown the importance of TGF-β family members and their adaptor proteins in the inhibition of proliferation in the nervous system. Previously, we have demonstrated that TGF-β induces phosphorylation and association of ELF (embryonic liver fodrin) with Smad3 and Smad4 resulting in nuclear translocation. Elf-/- mice manifest abnormal neuronal differentiation, with loss of neuroepithelial progenitor cell phenotype in the subventricular zone (SVZ) with dramatic marginal cell hyperplasia and loss of nestin expression. Here, we have analyzed the expression of cell cycle-associated proteins cdk4, mdm2, p21, and pRb family members in the brain of elf-/- mice to verify the role of elf in the regulation of neural precursor cells in the mammalian brain. Increased proliferation in SVZ cells of the mutant mice coincided with higher levels of cdk4 and mdm2 expression. A lesser degree of apoptosis was observed in the mutant mice compared to the wild-type control. Elf-/- embryos showed elevated levels of hyperphosphorylated forms of pRb, p130 and p107 and decreased level of p21 compared to the wild-type control. These results establish a critical role for elf in the development of a SVZ neuroepithelial stem cell phenotype and regulation of neuroepithelial cell proliferation, suggesting that a mutation in the elf locus renders the cells susceptible to a faster entry into S phase of cell cycle and resistance to senescence and apoptotic stimuli.

Original languageEnglish (US)
Pages (from-to)45-53
Number of pages9
JournalBrain Research
Volume1108
Issue number1
DOIs
StatePublished - Sep 7 2006
Externally publishedYes

Fingerprint

Lateral Ventricles
Neuroepithelial Cells
Cell Cycle
Stem Cells
Phenotype
Brain
Nestin
Cell Cycle Proteins
Neural Stem Cells
Prosencephalon
S Phase
Nervous System
Hyperplasia
Embryonic Structures
Phosphorylation
Cell Proliferation
Apoptosis
Mutation
Liver
Proteins

Keywords

  • cdk4
  • Cyclin D1
  • mdm2
  • p21
  • pRb
  • Smad
  • TGF-β

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Neurology
  • Developmental Biology
  • Molecular Biology

Cite this

Cell cycle deregulation and loss of stem cell phenotype in the subventricular zone of TGF-β adaptor elf-/- mouse brain. / Golestaneh, Nady; Tang, Yi; Katuri, Varalakshmi; Jogunoori, Wilma; Mishra, Lopa; Mishra, Bibhuti.

In: Brain Research, Vol. 1108, No. 1, 07.09.2006, p. 45-53.

Research output: Contribution to journalArticle

Golestaneh, Nady ; Tang, Yi ; Katuri, Varalakshmi ; Jogunoori, Wilma ; Mishra, Lopa ; Mishra, Bibhuti. / Cell cycle deregulation and loss of stem cell phenotype in the subventricular zone of TGF-β adaptor elf-/- mouse brain. In: Brain Research. 2006 ; Vol. 1108, No. 1. pp. 45-53.
@article{d8a077bd57ff40948bbb5058069bce32,
title = "Cell cycle deregulation and loss of stem cell phenotype in the subventricular zone of TGF-β adaptor elf-/- mouse brain",
abstract = "The mammalian forebrain subependyma contains neural stem cells and other proliferating progenitor cells. Recent studies have shown the importance of TGF-β family members and their adaptor proteins in the inhibition of proliferation in the nervous system. Previously, we have demonstrated that TGF-β induces phosphorylation and association of ELF (embryonic liver fodrin) with Smad3 and Smad4 resulting in nuclear translocation. Elf-/- mice manifest abnormal neuronal differentiation, with loss of neuroepithelial progenitor cell phenotype in the subventricular zone (SVZ) with dramatic marginal cell hyperplasia and loss of nestin expression. Here, we have analyzed the expression of cell cycle-associated proteins cdk4, mdm2, p21, and pRb family members in the brain of elf-/- mice to verify the role of elf in the regulation of neural precursor cells in the mammalian brain. Increased proliferation in SVZ cells of the mutant mice coincided with higher levels of cdk4 and mdm2 expression. A lesser degree of apoptosis was observed in the mutant mice compared to the wild-type control. Elf-/- embryos showed elevated levels of hyperphosphorylated forms of pRb, p130 and p107 and decreased level of p21 compared to the wild-type control. These results establish a critical role for elf in the development of a SVZ neuroepithelial stem cell phenotype and regulation of neuroepithelial cell proliferation, suggesting that a mutation in the elf locus renders the cells susceptible to a faster entry into S phase of cell cycle and resistance to senescence and apoptotic stimuli.",
keywords = "cdk4, Cyclin D1, mdm2, p21, pRb, Smad, TGF-β",
author = "Nady Golestaneh and Yi Tang and Varalakshmi Katuri and Wilma Jogunoori and Lopa Mishra and Bibhuti Mishra",
year = "2006",
month = "9",
day = "7",
doi = "10.1016/j.brainres.2006.05.113",
language = "English (US)",
volume = "1108",
pages = "45--53",
journal = "Brain Research",
issn = "0006-8993",
publisher = "Elsevier",
number = "1",

}

TY - JOUR

T1 - Cell cycle deregulation and loss of stem cell phenotype in the subventricular zone of TGF-β adaptor elf-/- mouse brain

AU - Golestaneh, Nady

AU - Tang, Yi

AU - Katuri, Varalakshmi

AU - Jogunoori, Wilma

AU - Mishra, Lopa

AU - Mishra, Bibhuti

PY - 2006/9/7

Y1 - 2006/9/7

N2 - The mammalian forebrain subependyma contains neural stem cells and other proliferating progenitor cells. Recent studies have shown the importance of TGF-β family members and their adaptor proteins in the inhibition of proliferation in the nervous system. Previously, we have demonstrated that TGF-β induces phosphorylation and association of ELF (embryonic liver fodrin) with Smad3 and Smad4 resulting in nuclear translocation. Elf-/- mice manifest abnormal neuronal differentiation, with loss of neuroepithelial progenitor cell phenotype in the subventricular zone (SVZ) with dramatic marginal cell hyperplasia and loss of nestin expression. Here, we have analyzed the expression of cell cycle-associated proteins cdk4, mdm2, p21, and pRb family members in the brain of elf-/- mice to verify the role of elf in the regulation of neural precursor cells in the mammalian brain. Increased proliferation in SVZ cells of the mutant mice coincided with higher levels of cdk4 and mdm2 expression. A lesser degree of apoptosis was observed in the mutant mice compared to the wild-type control. Elf-/- embryos showed elevated levels of hyperphosphorylated forms of pRb, p130 and p107 and decreased level of p21 compared to the wild-type control. These results establish a critical role for elf in the development of a SVZ neuroepithelial stem cell phenotype and regulation of neuroepithelial cell proliferation, suggesting that a mutation in the elf locus renders the cells susceptible to a faster entry into S phase of cell cycle and resistance to senescence and apoptotic stimuli.

AB - The mammalian forebrain subependyma contains neural stem cells and other proliferating progenitor cells. Recent studies have shown the importance of TGF-β family members and their adaptor proteins in the inhibition of proliferation in the nervous system. Previously, we have demonstrated that TGF-β induces phosphorylation and association of ELF (embryonic liver fodrin) with Smad3 and Smad4 resulting in nuclear translocation. Elf-/- mice manifest abnormal neuronal differentiation, with loss of neuroepithelial progenitor cell phenotype in the subventricular zone (SVZ) with dramatic marginal cell hyperplasia and loss of nestin expression. Here, we have analyzed the expression of cell cycle-associated proteins cdk4, mdm2, p21, and pRb family members in the brain of elf-/- mice to verify the role of elf in the regulation of neural precursor cells in the mammalian brain. Increased proliferation in SVZ cells of the mutant mice coincided with higher levels of cdk4 and mdm2 expression. A lesser degree of apoptosis was observed in the mutant mice compared to the wild-type control. Elf-/- embryos showed elevated levels of hyperphosphorylated forms of pRb, p130 and p107 and decreased level of p21 compared to the wild-type control. These results establish a critical role for elf in the development of a SVZ neuroepithelial stem cell phenotype and regulation of neuroepithelial cell proliferation, suggesting that a mutation in the elf locus renders the cells susceptible to a faster entry into S phase of cell cycle and resistance to senescence and apoptotic stimuli.

KW - cdk4

KW - Cyclin D1

KW - mdm2

KW - p21

KW - pRb

KW - Smad

KW - TGF-β

UR - http://www.scopus.com/inward/record.url?scp=33748805234&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33748805234&partnerID=8YFLogxK

U2 - 10.1016/j.brainres.2006.05.113

DO - 10.1016/j.brainres.2006.05.113

M3 - Article

VL - 1108

SP - 45

EP - 53

JO - Brain Research

JF - Brain Research

SN - 0006-8993

IS - 1

ER -