Overexpression of p27Kip1 lengthens the G1 phase in a mouse model that targets inducible gene expression to central nervous system progenitor cells.
We describe a mouse model in which p27(Kip1) transgene expression is spatially restricted to the central nervous system neuroepithelium and temporally controlled with doxycycline. Transgene-specific transcripts are detectable within 6 h of doxycycline administration, and maximum nonlethal expression is approached within 12 h. After 18-26 h of transgene expression, the G(1) phase of the cell cycle is estimated to increase from 9 to 13 h in the neocortical neuroepithelium, the maximum G(1) phase length attainable in this proliferative population in normal mice. Thus our data establish a direct link between p27(Kip1) and control of G(1) phase length in the mammalian central nervous system and unveil intrinsic mechanisms that constrain the G(1) phase length to a putative physiological maximum despite ongoing p27(Kip1) transgene expression.
Mitsuhashi
T
T
Department of Developmental Neurobiology, Central Nervous System Signaling Laboratory, Center for Aging, Genetics, and Neurodegeneration, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
Aoki
Y
Y
Eksioglu
Y Z
YZ
Takahashi
T
T
Bhide
P G
PG
Reeves
S A
SA
Caviness
V S
VS
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D017209:Apoptosis; D002453:Cell Cycle; D018797:Cell Cycle Proteins; D002490:Central Nervous System / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D002540:Cerebral Cortex / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004305:Dose-Response Relationship, Drug; D004318:Doxycycline / Q000494:pharmacology; D004848:Epithelium; D016193:G1 Phase; D015870:Gene Expression; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis* / Q000235:genetics; D008938:Mitosis; D008954:Models, Biological; D019579:Neocortex / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D013234:Stem Cells; D019076:Transgenes; D025521:Tumor Suppressor Proteins
D000900:Anti-Bacterial Agents; C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D008869:Microtubule-Associated Proteins; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004318:Doxycycline