Search

Your search keyword '"Rajaganapathi, Jagannathan"' showing total 4 results
Start Over Author "Rajaganapathi, Jagannathan" Publication Year Range Last 3 years
4 results on '"Rajaganapathi, Jagannathan"'

1. Myoglobin modulates the Hippo pathway to promote cardiomyocyte differentiation

Author

Krithika Rao, Elizabeth Rochon, Anuradha Singh, Rajaganapathi Jagannathan, Zishan Peng, Haris Mansoor, Bing Wang, Mousumi Moulik, Manling Zhang, Anita Saraf, Paola Corti, and Sruti Shiva

Subjects
Natural sciences, Biological sciences, Biochemistry, Cell biology, Specialized functions of cells, Science
Abstract

Summary: The endogenous mechanisms that propagate cardiomyocyte differentiation and prevent de-differentiation remain unclear. While the expression of the heme protein myoglobin increases by over 50% during cardiomyocyte differentiation, a role for myoglobin in regulating cardiomyocyte differentiation has not been tested. Here, we show that deletion of myoglobin in cardiomyocyte models decreases the gene expression of differentiation markers and stimulates cellular proliferation, consistent with cardiomyocyte de-differentiation. Mechanistically, the heme prosthetic group of myoglobin catalyzes the oxidation of the Hippo pathway kinase LATS1, resulting in phosphorylation and inactivation of yes-associated protein (YAP). In vivo, myoglobin-deficient zebrafish hearts show YAP dephosphorylation and accelerated cardiac regeneration after apical injury. Similarly, myoglobin knockdown in neonatal murine hearts shows increased YAP dephosphorylation and cardiomyocyte cycling. These data demonstrate a novel role for myoglobin as an endogenous driver of cardiomyocyte differentiation and highlight myoglobin as a potential target to enhance cardiac development and improve cardiac repair and regeneration.

Published
2024
Full Text
View/download PDF

2. VGLL4 and MENIN function as TEAD1 corepressors to block pancreatic β cell proliferation

Author

Feng Li, Ruya Liu, Vinny Negi, Ping Yang, Jeongkyung Lee, Rajaganapathi Jagannathan, Mousumi Moulik, and Vijay K. Yechoor

Subjects
CP: Cell biology, CP: Metabolism, Biology (General), QH301-705.5
Abstract

Summary: TEAD1 and the mammalian Hippo pathway regulate cellular proliferation and function, though their regulatory function in β cells remains poorly characterized. In this study, we demonstrate that while β cell-specific TEAD1 deletion results in a cell-autonomous increase of β cell proliferation, β cell-specific deletion of its canonical coactivators, YAP and TAZ, does not affect proliferation, suggesting the involvement of other cofactors. Using an improved split-GFP system and yeast two-hybrid platform, we identify VGLL4 and MENIN as TEAD1 corepressors in β cells. We show that VGLL4 and MENIN bind to TEAD1 and repress the expression of target genes, including FZD7 and CCN2, which leads to an inhibition of β cell proliferation. In conclusion, we demonstrate that TEAD1 plays a critical role in β cell proliferation and identify VGLL4 and MENIN as TEAD1 corepressors in β cells. We propose that these could be targeted to augment proliferation in β cells for reversing diabetes.

Published
2023
Full Text
View/download PDF

3. Abstract P1038: Role Of Hypomorphic Notch1 Mutations In Cardiomyocyte Signaling And Function In Hypoplastic Left Heart Syndrome

Author

Saraf, Anita, primary, Brent, Schlegel, additional, Zaineb, Javed, additional, Rao, Krithika, additional, Lear, Travis, additional, Rajaganapathi, Jagannathan, additional, Moulik, Mousumi, additional, Nadine, Hempel, additional, Shiva, Sruti, additional, Rajasundaram, Dhivyaa, additional, Kuhn, Bernhard, additional, and Finkel, Toren, additional

Published
2023
Full Text
View/download PDF

4. 250-LB: Tead1—A Regulator of Adult ß-Cell Proliferation and Function

Author

JEONGKYUNG LEE, RUYA LIU, FENG LI, VINNY NEGI, RAJAGANAPATHI JAGANNATHAN, MARK HUISING, KE MA, BEN SHIH, MOUSUMI MOULIK, and VIJAY YECHOOR

Subjects
Endocrinology, Diabetes and Metabolism, Internal Medicine
Abstract

The transcriptional factor, Tead1, mediates the transcriptional output of the Hippo pathway. Tead1 activates the transcription of downstream genes including many cell cycle promoting genes that lead to cell proliferation in many tissues, but its role in β-cells is unknown. To test if Tead1 is required for β-cell proliferation and function, we deleted Tead1 in β-cell. Deletion of Tead1 in β-cells was confirmed in these β-cell Tead1 KO (β-Tead1-/-) , by a significant decrease in transcript and protein from whole islet lysates. The β-Tead1-/- mice had normal body weight but developed significantly higher fasting and fed glucose levels starting at 5 weeks of age and progressed to frank diabetes by 8 weeks, with fasting blood glucose >300 mg/dl, accompanied by hypoinsulinemia, as compared to floxed control mice. 8wk β-Tead1-/- mice display severe glucose intolerance due to an abrogation of GSIS during GTT, with a loss of first phase insulin secretion. Pancreatic insulin content was decreased by ∼50%, due to a decrease in expression of mature β-cell genes including, Pdx1, Nkx6.1 and MafA, all of which, we show to be direct transcriptional targets of Tead1. Tead1 also binds to the proximal promoter at the Ink4a locus to regulate p16/p19, critical cell cycle inhibitors, and this loss of activation in Tead1-deficient β-cells leads to an enhanced entry into cell cycle. Furthermore, to test if Tead1 has a similar regulatory role in human β-cells, we deleted TEAD1 knockout in human iPS cell-derived β-cells using CRISPR/Cas9 system. Tead1 deficient iPS cell-derived β-cells displayed a significant decrease in vitro GSIS. Our results demonstrate Tead1 to be a transcriptional switch required for β-cells to maintain mature function and remain in proliferative quiescence. This novel regulatory pathway could be targeted for β-cell replacement therapy to achieve β-cell proliferation without a loss of mature function. Disclosure J. Lee: None. V. Yechoor: n/a. R. Liu: None. F. Li: None. V. Negi: None. R. Jagannathan: None. M. Huising: Consultant; Crinetics Pharmaceuticals, Inc., Research Support; Crinetics Pharmaceuticals, Inc. K. Ma: None. B. Shih: None. M. Moulik: None. Funding VA-MERIT Grant (I01BX002678)

Published
2022
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results