Biology subjects

Sifuentes, C. J.

Publications and source records attributed to Sifuentes, C. J..

2 recordsLinked to original sources

bioRxiv2019

Midkine-a is required for cell cycle progression of Müller glia during neuronal regeneration

In zebrafish, Muller glia function as intrinsic retinal stem cells that can regenerate ablated neurons. Understanding the mechanisms governing neuronal stem cells may provide clues to regenerate neurons in mammals. We report that in Muller glia the cytokine/growth factor, Midkine-a, functions as a core autocrine regulator of the cell cycle. Utilizing midkine-a mutants, we determined that Midkine-a regulates elements of an Id2a-retinoblastoma network in reprogrammed Muller glia that controls the expression of cell cycle genes and is required for transition from G1 to S phases of the cell cycle. In mutants, Muller glia that fail to divide undergo reactive gliosis, a pathological hallmark of Muller glia in mammals. Finally, we show that activation of the Midkine-a receptor, ALK, is required for Muller glia proliferation. These data provide mechanistic insights into Muller glia stem cells in the vertebrate retina and suggest avenues for eliciting neuronal regeneration in mammals.

developmental biology↗

bioRxiv2019

Two separation-of-function isoforms of human TPP1 and a novel intragenic noncoding RNA dictate telomerase regulation in somatic and germ cells.

Telomerase replicates chromosome ends in germ and somatic stem cells to facilitate continued proliferation. Telomerase action depends on the telomeric protein TPP1, which recruits telomerase to telomeres and facilitates processive DNA synthesis. Here we identify separation-of-function long (TPP1-L) and short (TPP1-S) isoforms of TPP1 differing only in 86 amino acids at their N-terminus. While both isoforms retain the ability to recruit telomerase, only TPP1-S facilitates telomere synthesis. We identify a novel intragenic noncoding RNA in the 3-UTR of the TPP1-encoding gene that specifically shuts down telomerase activation-incompatible TPP1-L to establish TPP1-S as the predominant isoform in somatic cells. Strikingly, TPP1-L is the major isoform in testes, where it can function to restrain telomerase in mature germ cells. Our studies uncover how differential expression of two isoforms allows TPP1 to perform separate functions in different cells, and demonstrate how isoform choice can be determined by an intragenic noncoding RNA.

biochemistry↗