High Commitment of Embryonic Keratinocytes to Terminal Differentiation through a Notch1-caspase 3 Regulatory Mechanism

Abstract

Embryonic cells are expected to possess high growth/differentiation potential, required for organ morphogenesis and expansion during development. However, little is known about the intrinsic properties of embryonic epithelial cells due to difficulties in their isolation and cultivation. We report here that pure keratinocyte populations from E15.5 mouse embryos commit irreversibly to differentiation much earlier than newborn cells. Notch signaling, which promotes keratinocyte differentiation, is upregulated in embryonic keratinocyte and epidermis, and elevated caspase 3 expression, which we identify as a transcriptional Notch1 target, accounts in part for the high commitment of embryonic keratinocytes to terminal differentiation. In vivo, lack of caspase 3 results in increased proliferation and decreased differentiation of interfollicular embryonic keratinocytes, together with decreased activation of PKC-delta, a caspase 3 substrate which functions as a positive regulator of keratinocyte differentiation. Thus, a Notch1-caspase 3 regulatory mechanism underlies the intrinsically high commitment of embryonic keratinocytes to terminal differentiation.

Proliferation and cornification during development of the mammalian epidermis

“…The results of an examination of the dynamics of Brd-U labeling in E15.5 and newborn epidermis were consistent with E15.5 keratinocytes "transiting" at a faster rate toward terminal differentiation (Okuyama et al, 2004). In addition, levels of activated Notch and caspase 3 were significantly higher in embryonic than in newborn epidermis.…”

“…Conditional elimination of Notch1 from the basal layer of newborn epidermis results in significant epidermal thickening associated with increased proliferation, indicating a failure of cells to undergo growth arrest (Rangarajan et al, 2001). In mice, Notch1 and JAG-1 have been reported to be expressed as early as E15.5 in the developing epidermis (Okuyama et al, 2004), indicating that Notch signaling may be important for the initial growth arrest signals that allow the cells to enter a differentiation program.…”

Sustained JNK signaling by proteolytically processed HPK1 mediates IL-3 independent survival during monocytic differentiation

“…32 Commitment to terminal keratinocyte differentiation was reported to be mediated by a caspase-3 dependent inactivation of PKCd. 33 Further examples for non-apoptotic caspase activities include erythrocyte differentiation, 34 platelet formation 35 or T-cell activation and proliferation. 36,37 A caspase-like activity was also found to be required for survival of dendritic cells and control of dendritic cell maturation.…”

Does Notch play a tumor suppressor role across diverse squamous cell carcinomas?

“…Lack of caspase 3 resulted in increased proliferation and decreased differentiation of embryonic keratinocytes 36. However, the possible involvement of this pathway in CSCC remains to be clarified, although increased expression of survivin, an apoptosis inhibitor targeting caspase 3 and caspase 7, was observed in CSCC tumors 37, 38, 39.…”