Davaapil H et al. (2017), Conserved and novel functions of programmed cel...

XB-ART-52787

Development 2017 Jan 01;1441:106-114. doi: 10.1242/dev.138222.

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Conserved and novel functions of programmed cellular senescence during vertebrate development.

Davaapil H , Brockes JP , Yun MH .

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Cellular senescence, a form of stable cell cycle arrest that is traditionally associated with tumour suppression, has been recently found to occur during mammalian development. Here, we show that cell senescence is an intrinsic part of the developmental programme in amphibians. Programmed senescence occurs in specific structures during defined time windows during amphibian development. It contributes to the physiological degeneration of the amphibian pronephros and to the development of the cement gland and oral cavity. In both contexts, senescence depends on TGFβ but is independent of ERK/MAPK activation. Furthermore, elimination of senescent cells through temporary TGFβ inhibition leads to developmental defects. Our findings uncover conserved and new roles of senescence in vertebrate organogenesis and support the view that cellular senescence may have arisen in evolution as a developmental mechanism.

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Species referenced: Xenopus laevis
Genes referenced: mapk1 smad3

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Fig. 3. Programmed cellular senescence during Xenopus laevis development. (A-K) Representative images of SAβgal staining of whole-mount Xenopus embryos at the indicated developmental stages (n=8 per stage). (A,B) Xenopus embryos, NF 46 (A) and NF 49 (B). (C) Xenopus pronephros, NF 49. (D-F) Xenopus brains at NF 46 (D), NF 49 (E) and NF 52 (F). (G-I) Xenopus anterior cartilage at NF 46 (G), NF 49 (H) and NF 52 (I). (J,K) Xenopus pronephros at NF 46 (J) and NF 49 (K). Senescence is absent in brain and cartilage at NF 46 and NF 52. c, cartilage; cg, cement gland; hb, hindbrain; mb, midbrain; p, pronephros. Scale bars: 100 µm in C; 50 µm in D-K. (L-N) Representative cryosections of Xenopus pronephros at NF 46 (SAβgal negative, L) and NF 51 (SAβgal positive, M and N) following staining with E. cristagalli lectin, DAPI and the indicated antibodies. Scale bar: 50 µm.

Fig. 4. Inhibition of TGFβ signalling abrogates cellular senescence in Xenopus laevis cement gland, leading to morphogenetic alterations in neighbouring structures. (A) SAβgal staining of whole-mount Xenopus embryos at NF 45 following treatment with the indicated inhibitors, from stage 24 onwards. Arrows indicate the cement gland. Positive signal is present in the control tadpoles (n=6). (B) Representative paraffin wax-embedded sections following SAβgal/Haematoxylin and Eosin co-staining. Senescent cells are absent and the cement gland is smaller in animals treated with the TGFβ inhibitor 1. Scale bar: 50 µm. (C) Quantification of number of SAβgal-positive cells per area (µm2) in NF 45 tadpoles following treatment with the indicated inhibitors, from stage 24 onwards (n=4, **P<0.01). Data are mean±s.e.m. (D) Western blot analysis of tadpole extracts following the indicated treatments. Phospho-Smad3 levels decrease only upon treatment with TGFβ inhibitor 1 (n=5). (E) Representative images of the anterior region of Xenopus embryos at NF 45 following the indicated treatments. Abrogation of cellular senescence through TGFβ inhibition results in a substantial shortening of the mouth (red dotted lines) (n=8). (F) Quantification of average mouth length in NF 46 tadpoles treated with vehicle (DMSO) or TGFβ inhibitor 1 (n=8, **P<0.01). Data are mean±s.e.m.

References [+] :

Acosta, A complex secretory program orchestrated by the inflammasome controls paracrine senescence. 2013, Pubmed