The apical complex couples cell fate and cell survival to cerebral cortical development.
Cortical development depends upon tightly controlled cell fate and cell survival decisions that generate a functional neuronal population, but the coordination of these two processes is poorly understood. Here we show that conditional removal of a key apical complex protein, Pals1, causes premature withdrawal from the cell cycle, inducing excessive generation of early-born postmitotic neurons followed by surprisingly massive and rapid cell death, leading to the abrogation of virtually the entire cortical structure. Pals1 loss shows exquisite dosage sensitivity, so that heterozygote mutants show an intermediate phenotype on cell fate and cell death. Loss of Pals1 blocks essential cell survival signals, including the mammalian target of rapamycin (mTOR) pathway, while mTORC1 activation partially rescues Pals1 deficiency. These data highlight unexpected roles of the apical complex protein Pals1 in cell survival through interactions with mTOR signaling.
Kim
Seonhee
S
Howard Hughes Medical Institute, Beth Israel Deaconess Medical Center, Division of Genetics, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA.
Lehtinen
Maria K
MK
Sessa
Alessandro
A
Zappaterra
Mauro W
MW
Cho
Seo-Hee
SH
Gonzalez
Dilenny
D
Boggan
Brigid
B
Austin
Christina A
CA
Wijnholds
Jan
J
Gambello
Michael J
MJ
Malicki
Jarema
J
LaMantia
Anthony S
AS
Broccoli
Vania
V
Walsh
Christopher A
CA
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D002470:Cell Survival / Q000235:genetics; D002540:Cerebral Cortex / Q000166:cytology / Q000254:growth & development / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D018390:Gene Targeting; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D008822:Mice, Transgenic; D055495:Neurogenesis / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D009703:Nucleoside-Phosphate Kinase; D038081:Organogenesis / Q000235:genetics / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases
D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C546843:mTOR protein, mouse; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D009703:Nucleoside-Phosphate Kinase; C499979:Mpp5 protein, mouse
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