PMID- 36824760
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20240214
DP  - 2023 Feb 15
TI  - Dephosphorylation of 4EBP1/2 Induces Prenatal Neural Stem Cell Quiescence.
LID - 2023.02.14.528513 [pii]
LID - 10.1101/2023.02.14.528513 [doi]
AB  - A limiting factor in the regenerative capacity of the adult brain is the 
      abundance and proliferative ability of neural stem cells (NSCs). Adult NSCs are 
      derived from a subpopulation of embryonic NSCs that temporarily enter quiescence 
      during mid-gestation and remain quiescent until postnatal reactivation. Here we 
      present evidence that the mechanistic/mammalian target of rapamycin (mTOR) 
      pathway regulates quiescence entry in embryonic NSCs of the developing forebrain. 
      Throughout embryogenesis, two downstream effectors of mTOR, p-4EBP1/2 T37/46 and 
      p-S6 S240/244, were mutually exclusive in NSCs, rarely occurring in the same 
      cell. While 4EBP1/2 was phosphorylated in stem cells undergoing mitosis at the 
      ventricular surface, S6 was phosphorylated in more differentiated cells migrating 
      away from the ventricle. Phosphorylation of 4EBP1/2, but not S6, was responsive 
      to quiescence induction in cultured embryonic NSCs. Further, inhibition of 
      p-4EBP1/2, but not p-S6, was sufficient to induce quiescence. Collectively, this 
      work offers new insight into the regulation of quiescence entry in embryonic NSCs 
      and, thereby, correct patterning of the adult brain. These data suggest unique 
      biological functions of specific posttranslational modifications and indicate 
      that the preferential inhibition of such modifications may be a useful 
      therapeutic approach in neurodevelopmental diseases where NSC numbers, 
      proliferation, and differentiation are altered.
FAU - Geben, Laura C
AU  - Geben LC
AD  - Program in Pharmacology, Vanderbilt University, Nashville, TN, 37235, USA.
AD  - Department of Cell and Developmental Biology, Vanderbilt University, Nashville, 
      TN, 37235, USA.
FAU - Brockman, Asa A
AU  - Brockman AA
AD  - Department of Cell and Developmental Biology, Vanderbilt University, Nashville, 
      TN, 37235, USA.
FAU - Chalkley, Mary Bronwen L
AU  - Chalkley MBL
AD  - Department of Cell and Developmental Biology, Vanderbilt University, Nashville, 
      TN, 37235, USA.
FAU - Sweet, Serena R
AU  - Sweet SR
AD  - Department of Molecular Physiology and Biophysics, Vanderbilt University, 
      Nashville, TN 37235, USA.
FAU - Gallagher, Julia E
AU  - Gallagher JE
AD  - Department of Cell and Developmental Biology, Vanderbilt University, Nashville, 
      TN, 37235, USA.
FAU - Scheuing, Alexandra L
AU  - Scheuing AL
AD  - Department of Cell and Developmental Biology, Vanderbilt University, Nashville, 
      TN, 37235, USA.
FAU - Simerly, Richard B
AU  - Simerly RB
AD  - Department of Molecular Physiology and Biophysics, Vanderbilt University, 
      Nashville, TN 37235, USA.
AD  - Vanderbilt Brain Institute, Vanderbilt University, Nashville TN 37235, USA.
FAU - Ess, Kevin C
AU  - Ess KC
AD  - Department of Cell and Developmental Biology, Vanderbilt University, Nashville, 
      TN, 37235, USA.
AD  - Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 
      37235, USA.
AD  - Vanderbilt Brain Institute, Vanderbilt University, Nashville TN 37235, USA.
FAU - Irish, Jonathan M
AU  - Irish JM
AD  - Department of Cell and Developmental Biology, Vanderbilt University, Nashville, 
      TN, 37235, USA.
AD  - Department of Pathology, Microbiology and Immunology, Vanderbilt University 
      Medical Center, Nashville, TN 37235, USA.
AD  - Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, 
      TN 37235, USA.
FAU - Ihrie, Rebecca A
AU  - Ihrie RA
AD  - Department of Cell and Developmental Biology, Vanderbilt University, Nashville, 
      TN, 37235, USA.
AD  - Department of Neurological Surgery, Vanderbilt University Medical Center, 
      Nashville, TN 37235, USA.
AD  - Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, 
      TN 37235, USA.
AD  - Vanderbilt Brain Institute, Vanderbilt University, Nashville TN 37235, USA.
LA  - eng
GR  - T32 GM007628/GM/NIGMS NIH HHS/United States
GR  - F31 HD106890/HD/NICHD NIH HHS/United States
GR  - P30 DK058404/DK/NIDDK NIH HHS/United States
GR  - R01 NS118580/NS/NINDS NIH HHS/United States
GR  - P30 EY008126/EY/NEI NIH HHS/United States
GR  - P30 DK020593/DK/NIDDK NIH HHS/United States
GR  - P30 CA068485/CA/NCI NIH HHS/United States
GR  - R01 DK106476/DK/NIDDK NIH HHS/United States
GR  - F31 NS120608/NS/NINDS NIH HHS/United States
GR  - R01 NS096238/NS/NINDS NIH HHS/United States
GR  - U24 DK059637/DK/NIDDK NIH HHS/United States
GR  - T32 HD007502/HD/NICHD NIH HHS/United States
GR  - U54 CA217450/CA/NCI NIH HHS/United States
GR  - R01 CA226833/CA/NCI NIH HHS/United States
PT  - Preprint
DEP - 20230215
PL  - United States
TA  - bioRxiv
JT  - bioRxiv : the preprint server for biology
JID - 101680187
PMC - PMC9948964
EDAT- 2023/02/25 06:00
MHDA- 2023/02/25 06:01
PMCR- 2023/02/23
CRDT- 2023/02/24 02:57
PHST- 2023/02/25 06:00 [pubmed]
PHST- 2023/02/25 06:01 [medline]
PHST- 2023/02/24 02:57 [entrez]
PHST- 2023/02/23 00:00 [pmc-release]
AID - 2023.02.14.528513 [pii]
AID - 10.1101/2023.02.14.528513 [doi]
PST - epublish
SO  - bioRxiv [Preprint]. 2023 Feb 15:2023.02.14.528513. doi: 
      10.1101/2023.02.14.528513.