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Ctip2 is a dynamic regulator of epidermal proliferation and differentiation by integrating EGFR and Notch signaling.

ABSTRACT: Epidermal morphogenesis results from a delicate balance between keratinocyte proliferation and differentiation, and this balance is perturbed upon deletion of transcription factor Ctip2. Here we demonstrate that Ctip2, in a cell autonomous manner, controls keratinocyte proliferation and cytoskeletal organization, and regulates the onset and maintenance of differentiation in keratinocytes in culture. Ctip2 integrates keratinocyte proliferation and the switch to differentiation by directly and positively regulating EGFR transcription in proliferating cells and Notch1 transcription in differentiating cells. In proliferative cells, the EGFR promoter is occupied by Ctip2, whereas Ctip2 is only recruited to the Notch1 promoter under differentiating conditions. Activation of EGFR signaling downregulates Ctip2 at the transcript level, whereas high calcium signaling triggers SUMOylation, ubiquitination and proteasomal degradation of Ctip2 at the protein level. Together, our findings demonstrate a novel mechanism(s) of Ctip2-mediated, coordinated control of epidermal proliferation and terminal differentiation, and identify a pathway of negative feedback regulation of Ctip2 during epidermal development.

SUBMITTER: Zhang LJ

PROVIDER: S-EPMC3575708 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Ctip2 is a dynamic regulator of epidermal proliferation and differentiation by integrating EGFR and Notch signaling.

Zhang Ling-juan LJ Bhattacharya Shreya S Leid Mark M Ganguli-Indra Gitali G Indra Arup K AK

Journal of cell science 20120926 Pt 23

Epidermal morphogenesis results from a delicate balance between keratinocyte proliferation and differentiation, and this balance is perturbed upon deletion of transcription factor Ctip2. Here we demonstrate that Ctip2, in a cell autonomous manner, controls keratinocyte proliferation and cytoskeletal organization, and regulates the onset and maintenance of differentiation in keratinocytes in culture. Ctip2 integrates keratinocyte proliferation and the switch to differentiation by directly and pos ...[more]

PMID: 23015591

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Project description:BackgroundNotch signaling involves ligand-receptor interactions through direct cell-cell contact. Multiple Notch receptors and ligands are expressed in the epidermis and hair follicles during embryonic development and the adult stage. Although Notch signaling plays an important role in regulating differentiation of the epidermis and hair follicles, it remains unclear how Notch signaling participates in late-stage epidermal differentiation and postnatal hair cycle homeostasis.Methodology and principal findingsWe applied Cre/loxP system to generate conditional gene targeted mice that allow inactivation of critical components of Notch signaling pathway in the skin. Rbpj, the core component of all four Notch receptors, and Pofut1, an essential factor for ligand-receptor interactions, were inactivated in hair follicle lineages and suprabasal layer of the epidermis using the Tgfb3-Cre mouse line. Rbpj conditional inactivation resulted in granular parakeratosis and reactive epidermal hyperplasia. Pofut1 conditional inactivation led to ultrastructural abnormalities in the granular layer and altered filaggrin processing in the epidermis, suggesting a perturbation of the granular layer differentiation. Disruption of Pofut1 in hair follicle lineages resulted in aberrant telogen morphology, a decrease of bulge stem cell markers, and a concomitant increase of K14-positive keratinocytes in the isthmus of mutant hair follicles. Pofut1-deficent hair follicles displayed a delay in anagen re-entry and dysregulation of proliferation and apoptosis during the hair cycle transition. Moreover, increased DNA double stand breaks were detected in Pofut1-deficent hair follicles, and real time PCR analyses on bulge keratinocytes isolated by FACS revealed an induction of DNA damage response and a paucity of DNA repair machinery in mutant bulge keratinocytes.Significanceour data reveal a role for Notch signaling in regulating late-stage epidermal differentiation. Notch signaling is required for postnatal hair cycle homeostasis by maintaining proper proliferation and differentiation of hair follicle stem cells.

Project description:Teleosts live in aquatic habitats, where they encounter ionic and acid-base fluctuations as well as infectious pathogens. To protect from these external challenges, the teleost epidermis is composed of living cells, including keratinocytes and ionocytes that maintain body fluid ionic homeostasis, and mucous cells that secret mucus. While ionocyte progenitors are known to be specified by Delta-Notch-mediated lateral inhibition during late gastrulation and early segmentation, it remains unclear how epidermal mucous cells (EMCs) are differentiated and maintained. Here, we show that Delta/Jagged-mediated activation of Notch signaling induces the differentiation of agr2-positive (agr2+) EMCs in zebrafish embryos during segmentation. We demonstrated that agr2+ EMCs contain cytoplasmic secretory granules and express muc5.1 and muc5.2. Reductions in agr2+ EMC number were observed in mib mutants and notch3 MOs-injected notch1a mutants, while increases in agr2+ cell number were detected in notch1a- and X-Su(H)/ANK-overexpressing embryos. Treatment with γ-secretase inhibitors further revealed that Notch signaling is required during bud to 15 hpf for the differentiation of agr2+ EMCs. Increased agr2+ EMC numbers were also observed in jag1a-, jag1b-, jag2a- and dlc-overexpressing, but not jag2b-overexpressing embryos. Meanwhile, reductions in agr2+ EMC numbers were detected in jag1a morphants, jag1b mutants, jag2a mutants and dlc morphants, but not jag2b mutants. Reduced numbers of pvalb8-positive epidermal cells were also observed in mib or jag2a mutants and jag1a or jag1b morphants, while increased pvalb8-positive epidermal cell numbers were detected in notch1a-overexpressing, but not dlc-overexpressing embryos. BrdU labeling further revealed that the agr2+ EMC population is maintained by proliferation. Cell lineage experiments showed that agr2+ EMCs are derived from the same ectodermal precursors as keratinocytes or ionocytes. Together, our results indicate that specification of agr2+ EMCs in zebrafish embryos is induced by DeltaC/Jagged-dependent activation of Notch1a/3 signaling, and the cell population is maintained by proliferation.

Dataset Information

Ctip2 is a dynamic regulator of epidermal proliferation and differentiation by integrating EGFR and Notch signaling.

Publications

Ctip2 is a dynamic regulator of epidermal proliferation and differentiation by integrating EGFR and Notch signaling.

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