Developmental Cell - TPP1 Is Required for TERT Recruitment, Telomere Elongation during Nuclear Reprogramming, and Normal Skin Development in Mice

Developmental Cell, Volume 18, Issue 5, 775-789, 18 May 2010 | Copyright 2010 Elsevier Inc. All rights reserved. | 10.1016/j.devcel.2010.03.011

TPP1 Is Required for TERT Recruitment, Telomere Elongation during Nuclear Reprogramming, and Normal Skin Development in Mice

Agueda M. Tejera, Martina Stagno d'Alcontres, Maria Thanasoula, Rosa M. Marion, Paula Martinez, Chunyan Liao, Juana M. Flores, Madalena Tarsounas, Maria A. Blasco

Summary
The TPP1/ACD protein (hereafter TPP1) is a component of the shelterin complex at mammalian telomeres. Here we find that Tpp1-deficient mouse embryonic fibroblasts (MEFs) show increased chromosomal instability including sister chromatid fusions and chromosomes with multitelomeric signals related to telomere fragility. Tpp1 deletion decreases both TERT (the telomerase catalytic subunit) binding to telomeres in MEFs and telomerase function at chromosome ends in vivo. Abrogation of Tpp1 abolished net telomere elongation in the context of nuclear reprogramming of MEFs into induced pluripotent stem cells, whereas Tpp1 deletion in stratified epithelia of Tpp1/K5-Cre mice resulted in perinatal death, severe skin hyperpigmentation, and impaired hair follicle morphogenesis. p53 deficiency rescues skin hyperpigmentation and hair growth in these mice, indicating that p53 restricts proliferation of Tpp1-deficient cells. These results suggest a telomere-capping model where TPP1 protects telomere integrity and regulates telomerase recruitment to telomeres, thereby preventing early occurrence of degenerative pathologies.

The TPP1/ACD protein (hereafter TPP1) is part of the shelterin complex bound to mammalian telomeres, encompassing TRF1, TRF2, POT1a/b, TPP1, TIN2, and RAP1 in the mouse (de Lange, 2005,Liu et al., 2004). Evidence from Schizosaccharomyces pombe and mammals suggests that TPP1 interacts with POT1 and that this interaction is important for telomerase regulation at chromosome ends and for bridging TRF1 and TRF2 complexes at the double-stranded telomeric repeats (Miyoshi et al., 2008,Xin et al., 2007). In addition, TPP1 is required for POT1 binding and protection of telomeres (Hockemeyer et al., 2007).

A spontaneous recessive mutation in a splice donor site of the Tpp1 gene is responsible for the acd mouse, a hypomorphic mouse model with decreased TPP1 levels (Keegan et al., 2005). These mice can survive to adulthood but show developmental defects including adrenocortical dysplasia and hypofunction, skin hyperpigmentation, and infertility (Keegan et al., 2005), as well as increased incidence of cancer in a p53 null background (Else et al., 2009). Cells derived from acd mice show increased telomere damage and telomere fusions but a normal telomere length (Else et al., 2007,Hockemeyer et al., 2007). A further understanding of the role of TPP1 in telomere regulation in vivo and in mouse development and disease has been missing to date due to lack of mouse models with complete TPP1 abrogation.

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Developmental Cell - TPP1 Is Required for TERT Recruitment, Telomere Elongation during Nuclear Reprogramming, and Normal Skin Development in Mice