TY  - UNPB
TI  - Lem2 is essential for cardiac development by maintaining nuclear integrity
ID  - uneatlantico622
AV  - public
A1  - Ross, Jacob A.
A1  - Arcos-Villacis, Nathaly
A1  - Battey, Edmund
A1  - Boogerd, Cornelis
A1  - Marhuenda, Emilie
A1  - Hodzic, Didier
A1  - Prin, Fabrice
A1  - Mohun, Tim
A1  - Catibog, Norman
A1  - Tapia Martínez, Olga
A1  - Gerace, Larry
A1  - Iskratsch, Thomas
A1  - Shah, Ajay M.
A1  - Stroud, Matthew J.
Y1  - 2022/02//
JF  - bioRxiv
N2  - Nuclear envelope integrity is essential for compartmentalisation of nucleus and cytoplasm. Importantly, mutations in nuclear envelope-encoding genes are the second-highest cause of familial dilated cardiomyopathy. One such nuclear envelope protein that causes cardiomyopathy in humans and affects mouse heart development is Lem2. However, its role in mechanically active tissue such as heart remains poorly understood.

We generated mice in which Lem2 was specifically ablated in cardiomyocytes and carried out detailed physiological, tissue and cellular analyses. Importantly, our data showed that Lem2 was essential for cardiac development, and hearts from Lem2 cKO mice were morphologically and transcriptionally underdeveloped. Lem2 cKO hearts displayed high levels of DNA damage, nuclear rupture, and apoptosis. Crucially, we found that these defects were driven by muscle contraction as they were ameliorated by inhibiting myosin contraction and conversely were exacerbated upon myosin activation.

Our data suggest that Lem2 is critical for integrity at the nascent nuclear envelope in fetal hearts, and protects the nucleus from the mechanical forces of muscle contraction. Taken together, these data provide novel insight into mechanisms underlying striated muscle diseases caused by altered nuclear envelope integrity.
N1  - PREPRINT
UR  - http://doi.org/10.1101/2022.02.10.477501
ER  -