Phenotypes in mTERT^+/− and mTERT^−/− Mice Are Due to Short Telomeres, Not Telomere-Independent Functions of Telomerase Reverse Transcriptase

Abstract

Telomerase is essential for telomere length maintenance. Mutations in either of the two core components of telomerase, telomerase RNA (TR) or the catalytic protein component telomerase reverse transcriptase (TERT), cause the genetic disorders dyskeratosis congenita, pulmonary fibrosis, and other degenerative diseases. Overexpression of the TERT protein has been reported to have telomere length-independent roles, including regulation of the Wnt signaling pathway. To examine the phenotypes of TERT haploinsufficiency and determine whether loss of function of TERT has effects other than those associated with telomere shortening, we characterized both mTERT ؉/؊ and mTERT ؊/؊ mice on the CAST/EiJ genetic background. Phenotypic analysis showed a loss of tissue renewal capacity with progressive breeding of heterozygous mice that was indistinguishable from that of mTR-deficient mice. mTERT ؊/؊ mice, from heterozygous mTERT ؉/؊ mouse crosses, were born at the expected Mendelian ratio (26.5%; n ‫؍‬ 1,080 pups), indicating no embryonic lethality of this genotype. We looked for, and failed to find, hallmarks of Wnt deficiency in various adult and embryonic tissues, including those of the lungs, kidneys, brain, and skeleton. Finally, mTERT ؊/؊ cells showed wild-type levels of Wnt signaling in vitro. Thus, while TERT overexpression in some settings may activate the Wnt pathway, loss of function in a physiological setting has no apparent effects on Wnt signaling. Our results indicate that both TERT and TR are haploinsufficient and that their deficiency leads to telomere shortening, which limits tissue renewal. Our studies imply that hypomorphic loss-of-function alleles of hTERT and hTR should cause a similar disease spectrum in humans.

Human telomerase reverse transcriptase (hTERT) is a target gene of β-catenin in human colorectal tumors

“…But this finding is challenged by other studies, which did not confirm this function of hTERT. 45,46 Our results show that hTERT is a direct target gene of β-catenin and indicate, thereby, that the Wnt signaling pathway controls self-renewal and telomerase activity at the same time, 47 thereby linking two essential components in the biology of colorectal cancers.…”

TERT biology and function in cancer: beyond immortalisation

“…In mice mTERT +/− and mTERT −/− on the CAST/ EiJ genetic background, TERT overexpression in some settings may activate the Wnt pathways (Strong et al 2011). However, loss of function in a physiological setting has no apparent effects on Wnt signalling (Strong et al 2011).…”

“…However, loss of function in a physiological setting has no apparent effects on Wnt signalling (Strong et al 2011). This deficiency leads to telomere shortening, that limits tissue renewal, and these effects are not telomereindependent functions of TERT (Strong et al 2011).…”

Telomerase activates transcription of cyclin D1 gene through an interaction with NOL1

“…However, the proposed noncanonical role of TERT in the Wnt/β-catenin signaling cascade has been controversial. Several studies have reported a lack of physical association of TERT with BRG1 or β-catenin (Listerman et al, 2014), as well as no apparent effect of TERT deficiency on phenotypes associated with Wnt signaling in TERT-knockout mice (Strong et al, 2011). Although TERT appears to regulate the expression of growth-promoting genes, this event might not be solely promoted by Wnt signaling.…”