Targeted Deletion of all Caldesmon Splice Variants in Mice Results in Abdominal Wall Closure Defects

Abstract

Ample evidence obtained in vitro indicates that the thin filament linked protein, caldesmon (CaD) is involved in regulation of smooth muscle contraction. Homozygous h‐CaD deficient mice were reported to be viable and exhibit a but small slowing of relaxation (Guo et al., 2013). However, the results are confounded by upregulation of non‐muscle l‐CaD in smooth muscle. Thus, the in vivo function of CaD is still not clear. Here we report that deletion of all splice variants of Cald1 results in perinatal lethality whereas the life span of heterozygotes (hets) is normal. Gene targeting was achieved by deleting exons 2‐13 in the murine Cald1 gene. Homologous recombination was confirmed on DNA level by Southern blots and PCR, and on protein level by Western Blotting. Homozygous offspring followed Mendelian rules at E15.5 but was abrogated at E19.5. The bodyweight of the ‐/‐ fetuses at E18.5 was reduced by ~20%. The most prominent feature of the ‐/‐ fetuses is the persistence of the physiological umbilical hernia whereby the size of the abdominal wall defect is variable. Bladder contractility of adult hets was not significantly affected. In conclusion, our results indicate that deletion of CaD does not result in early embryonic lethality but it may be essential for organ maturation. Moreover, lack of h‐CaD but not lack of all splice variants including non‐muscle l‐CaD is compatible with life.

Identification of fifty-seven novel loci for abdominal wall hernia development and their biological and clinical implications: results from the UK Biobank

“…Some homozygous Cald1-mutant mice develop spontaneous hernias and die within 5-7 h after birth [15]. The Cald1 knockout fetuses have the persistence of the physiological umbilical hernia whereby the size of the abdominal wall defect is variable [16]. Here we found that risk alleles of 5 GWAS-significant SNPs are associated with decreased expression of CALD1 (Fig.…”