Biology subjects

Kyba, M.

Publications and source records attributed to Kyba, M..

3 recordsLinked to original sources

bioRxiv2018

Estrogen Regulates the Satellite Cell Compartment in Females

Skeletal muscle mass, strength, and regenerative capacity decline with age, with many measures showing greater deterioration in females about the time estrogen levels decrease at menopause. Here we show that maintenance of muscle stem cells, satellite cells, as well as self-renewal and differentiation into muscle fibers, are severely compromised by estrogen deficiency. Mechanistically, by hormone replacement, use of a selective estrogen-receptor modulator (bazedoxifene), and conditional estrogen receptor knockout, we implicate 17{beta}-estradiol and satellite cell expression of estrogen receptor (ER) and show that estrogen signaling through this receptor is necessary to prevent apoptosis of satellite cells. Early data from a biopsy study of women who transitioned from peri-to post-menopause are consistent with the loss of satellite cells coincident with the decline in estradiol in humans. Together, these results demonstrate an important role for estrogen in satellite cell maintenance and muscle regeneration in females.

cell biology↗

bioRxiv2018

Hedgehog signaling controls progenitor differentiation timing during heart development

Heterochrony, defined as differences in the timing of developmental processes, impacts organ development, homeostasis, and regeneration. The molecular basis of heterochrony in mammalian tissues is poorly understood. We report that Hedgehog signaling activates a heterochronic pathway that controls differentiation timing in multiple lineages. A differentiation trajectory from second heart field cardiac progenitors to first heart field cardiomyocytes was identified by single-cell transcriptional profiling in mouse embryos. A survey of developmental signaling pathways revealed specific enrichment for Hedgehog signaling targets in cardiac progenitors. Removal of Hh signaling caused loss of progenitor and precocious cardiomyocyte differentiation gene expression in the second heart field in vivo. Introduction of active Hh signaling to mESC-derived progenitors, modelled by transient expression of the Hh-dependent transcription factor GLI1, delayed differentiation in cardiac and neural lineages in vitro. A shared GLI1-dependent network in both cardiac and neural progenitors was enriched with FOX family transcription factors. FOXF1, a GLI1 target, was sufficient to delay onset of the cardiomyocyte differentiation program in progenitors, by epigenetic repression of cardiomyocyte-specific enhancers. Removal of active Hh signaling or Foxf1 expression from second heart field progenitors caused precocious cardiac differentiation in vivo, establishing a mechanism for resultant Congenital Heart Disease. Together, these studies suggest that Hedgehog signaling directly activates a gene regulatory network that functions as a heterochronic switch to control differentiation timing across developmental lineages.

developmental biology↗

bioRxiv2017

P53 is not necessary for DUX4 pathology

AbstractsFSHD is a genetically dominant myopathy caused by mutations that cause expression of the normally silent DUX4 gene. This transcription factor has been shown to interfere with myogenesis when misexpressed at very low levels in myoblasts, and to cause cell death when overexpressed at high levels. A previous report using adeno-associated virus to deliver high levels of DUX4 to mouse skeletal muscle demonstrated severe pathology that was suppressed on a p53 knockout background, implying that DUX4 acted through the p53 pathway. Here, we investigate the p53-dependence of DUX4 using both in vitro cellular and the transgenic iDUX4[2.7] mouse models. We find that inhibiting p53 has no effect on the cytoxicity of DUX4 in vitro. When crossed onto the p53 null background, we find no suppression of the male-specific lethality or skin phenotypes of the DUX4 transgene, and find that primary myoblasts from this mouse are still killed by DUX4 expression. These data challenge the notion that the p53 pathway is central to the pathogenicity of DUX4.\n\nSummary StatementDUX4 is thought to mediate cytopathology through p53. Here, DUX4 is shown to kill primary myoblasts and promote pathological phenotypes in the iDUX4[2.7] mouse model on the p53-null background, calling into question this notion.

genetics↗