Mechanisms of epithelial cell renewal remain poorly understood in the mammalian kidney, particularly in the glomerulus, a site of cellular damage in chronic kidney disease. Within the glomerulus, podocytes – differentiated epithelial cells critical for filtration – are thought to lack significant capacity for regeneration. Here, we show that podocytes rapidly lose differentiation markers and enter cell cycle in adult mice in which the telomerase protein component TERT is conditionally expressed. Transgenic TERT expression induces marked upregulation of Wnt signaling and disrupts glomerular structure resulting in a collapsing glomerulopathy resembling those in humans, including HIV-associated nephropathy (HIVAN). Human and mouse HIVAN kidneys show increased levels of TERT and activation of Wnt signaling, indicating that these are general features of collapsing glomerulopathies. Either silencing transgenic TERT expression or inhibition of Wnt signaling through systemic expression of the Wnt-inhibitor Dkk1 in TERT transgenic mice results in marked normalization of podocytes, including rapid cell cycle exit, re-expression of differentiation markers and improved filtration barrier function. These data reveal an unexpected property of podocytes to reversibly enter cell cycle, suggest that podocyte renewal may contribute to glomerular homeostasis and implicate the telomerase and Wnt/β-catenin pathways in podocyte proliferation and disease.

Sequencing of the complete mitochondrial genome of the soft coral Paraminabea aldersladei (Alcyoniidae) revealed a unique gene order, the fifth mt gene arrangement now known within the cnidarian subclass Octocorallia. At 19,886 bp, the mt genome of P. aldersladei is the second largest known for octocorals; its gene content and nucleotide composition are, however, identical to most other octocorals, and the additional length is due to the presence of two large, noncoding intergenic regions. Relative to the presumed ancestral octocoral gene order, in P. aldersladei a block of three protein-coding genes (nad6–nad3–nad4l) has been translocated and inverted. Mapping the distribution of mt gene arrangements onto a taxonomically comprehensive phylogeny of Octocorallia suggests that all of the known octocoral gene orders have evolved by successive inversions of one or more evolutionarily conserved blocks of protein-coding genes. This mode of genome evolution is unique among Metazoa, and contrasts strongly with that observed in Hexacorallia, in which extreme gene shuffling has occurred among taxonomic orders. Two of the four conserved gene blocks found in Octocorallia are, however, also conserved in the linear mt genomes of Medusozoa and in one group of Demospongiae. We speculate that the rate and mechanism of gene rearrangement in octocorals may be influenced by the presence in their mt genomes of mtMutS, a putatively active DNA mismatch repair protein that may also play a role in mediating intramolecular recombination.

Telomerase inactivation causes loss of the male germline in worms, fish, and mice, indicating a conserved dependence on telomere maintenance in this cell lineage. Here, using telomerase reverse transcriptase (Tert) reporter mice, we found that very high telomerase expression is a hallmark of undifferentiated spermatogonia, the mitotic population where germline stem cells reside. We exploited these high telomerase levels as a basis for purifying undifferentiated spermatogonia using fluorescence-activated cell sorting. Telomerase levels in undifferentiated spermatogonia and embryonic stem cells are comparable and much greater than in somatic progenitor compartments. Within the germline, we uncovered an unanticipated gradient of telomerase activity that also enables isolation of more mature populations. Transcriptomic comparisons of Tert High undifferentiated spermatogonia and Tert Low differentiated spermatogonia by RNA sequencing reveals marked differences in cell cycle and key molecular features of each compartment. Transplantation studies show that germline stem cell activity is confined to the Tert High cKit − population. Telomere shortening in telomerase knockout strains causes depletion of undifferentiated spermatogonia and eventual loss of all germ cells after undifferentiated spermatogonia drop below a critical threshold. These data reveal that high telomerase expression is a fundamental characteristic of germline stem cells, thus explaining the broad dependence on telomerase for germline immortality in metazoans.