Dataset Information

Dorsal-Ventral Differences in Neural Stem Cell Quiescence Are Induced by p57^KIP2/Dacapo.

ABSTRACT: Quiescent neural stem cells (NSCs) in the adult brain are regenerative cells that could be activated therapeutically to repair damage. It is becoming apparent that quiescent NSCs exhibit heterogeneity in their propensity for activation and in the progeny that they generate. We discovered recently that NSCs undergo quiescence in either G₀ or G₂ in the Drosophila brain, challenging the notion that all quiescent stem cells are G₀ arrested. We found that G₂-quiescent NSCs become activated prior to G₀ NSCs. Here, we show that the cyclin-dependent kinase inhibitor Dacapo (Dap; ortholog of p57^KIP2) determines whether NSCs enter G₀ or G₂ quiescence during embryogenesis. We demonstrate that the dorsal patterning factor, Muscle segment homeobox (Msh; ortholog of MSX1/2/3) binds directly to the Dap locus and induces Dap expression in dorsal NSCs, resulting in G₀ arrest, while more ventral NSCs undergo G₂ quiescence. Our results reveal region-specific regulation of stem cell quiescence.

SUBMITTER: Otsuki L

PROVIDER: S-EPMC6486397 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Dorsal-Ventral Differences in Neural Stem Cell Quiescence Are Induced by p57KIP2/Dacapo.

Otsuki Leo L Brand Andrea H AH

Developmental cell 20190321 2

Quiescent neural stem cells (NSCs) in the adult brain are regenerative cells that could be activated therapeutically to repair damage. It is becoming apparent that quiescent NSCs exhibit heterogeneity in their propensity for activation and in the progeny that they generate. We discovered recently that NSCs undergo quiescence in either G0 or G2 in the Drosophila brain, challenging the notion that all quiescent stem cells are G0 arrested. We found that G2</sub ...[more]

PMID: 30905769

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Project description:p57 is a member of the Cip/Kip family of cell cycle inhibitors which restrict the eukaryotic cell cycle by binding to and inhibiting cyclin/CDK complexes. They are considered as tumor suppressors and inactivating genomic mutations of p57 are associated with human overgrowth disorders. Increasing evidence suggests that p57 controls additional cellular processes beyond cell cycle control such as apoptosis, cell migration or transcription. Here we report that p57 can stimulate AP-1 promotor activity. While transactivation by c-Jun is strongly activated by p57, it did not enhance c-Fos induced transcription. This indicates that c-Jun is the target of p57 in the canonical AP-1 heterodimeric transcription factor. We could detect endogenous p57/c-Jun containing complexes in cells by co-immunoprecipitation. The strong stimulation of c-Jun activity is not the consequence of activating phosphorylation in the transactivation domain (TAD) of c-Jun, but rather due to negative interference with c-Jun repressors and positive interference with c-Jun activators. In contrast to full-length p57, the amino- and carboxy-terminal domains of p57 are insufficient for a significant activation of c-Jun induced transcription. When expressed in presence of full length p57, the p57 C-terminus abrogated and the N-terminus enhanced c-Jun activation. This indicates that the C-terminus may bind and sequester a putative activator of c-Jun, whereas the N-terminus may sequester a c-Jun repressor. Interestingly, the p57 aminoterminus is sufficient for binding to the two c-Jun repressors HDAC1 and HDAC3. These data are consistent with a model of c-Jun activation where p57 is a part of large nuclear remodeling/transcription complexes. p57 might stimulate transcription by inhibiting transcription repressor proteins like HDACs via its N-terminus and/or attracting transcription activators through its C-terminus. These data suggest that in addition to its role as a CDK inhibitor and tumor suppressor, p57 may also exert tumor promoting functions by activation of the proto-oncoprotein c-Jun.

Dataset Information

Dorsal-Ventral Differences in Neural Stem Cell Quiescence Are Induced by p57^KIP2/Dacapo.

Publications

Dorsal-Ventral Differences in Neural Stem Cell Quiescence Are Induced by p57<sup>KIP2</sup>/Dacapo.

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