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Disruption of the murine calpain small subunit gene, Capn4: calpain is essential for embryonic development but not for cell growth and division.

ABSTRACT: Calpains are a family of Ca(2+)-dependent intracellular cysteine proteases, including the ubiquitously expressed micro- and m-calpains. Both mu- and m-calpains are heterodimers, consisting of a distinct large 80-kDa catalytic subunit, encoded by the genes Capn1 and Capn2, and a common small 28-kDa regulatory subunit (Capn4). The physiological roles and possible functional distinctions of mu- and m-calpains remain unclear, but suggested functions include participation in cell division and migration, integrin-mediated signal transduction, apoptosis, and regulation of cellular control proteins such as cyclin D1 and p53. Homozygous disruption of murine Capn4 eliminated both mu- and m-calpain activities, but this did not affect survival and proliferation of cultured embryonic stem cells or embryonic fibroblasts, or the early stages of organogenesis. However, mutant embryos died at midgestation and displayed defects in the cardiovascular system, hemorrhaging, and accumulation of erythroid progenitors.

SUBMITTER: Arthur JS

PROVIDER: S-EPMC85815 | biostudies-literature | 2000 Jun

REPOSITORIES: biostudies-literature

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Disruption of the murine calpain small subunit gene, Capn4: calpain is essential for embryonic development but not for cell growth and division.

Arthur J S JS Elce J S JS Hegadorn C C Williams K K Greer P A PA

Molecular and cellular biology 20000601 12

Calpains are a family of Ca(2+)-dependent intracellular cysteine proteases, including the ubiquitously expressed micro- and m-calpains. Both mu- and m-calpains are heterodimers, consisting of a distinct large 80-kDa catalytic subunit, encoded by the genes Capn1 and Capn2, and a common small 28-kDa regulatory subunit (Capn4). The physiological roles and possible functional distinctions of mu- and m-calpains remain unclear, but suggested functions include participation in cell division and migrati ...[more]

PMID: 10825211

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Project description:Cell migration involves the dynamic formation and release of cell-substrate adhesions, where the exertion and detection of mechanical forces take place. Members of the calpain family of calcium-dependent proteases are believed to have a central role in these processes, possibly through the regulation of focal adhesion dynamics. The ubiquitous calpains, calpain 1 (mu-calpain) and calpain 2 (m-calpain), are heterodimers consisting of large catalytic subunits encoded by the Capn1 and Capn2 genes, respectively, and the small regulatory subunit encoded by Capn4. We have examined the role of the calpain regulatory small subunit in traction force production and mechanosensing during cell migration. Capn4-deficient or rescued cells were plated on flexible polyacrylamide substrates, for both the detection of traction forces and the application of mechanical stimuli. The total force output of Capn4-deficient cells was approximately 75% lower than that of rescued cells and the forces were more randomly distributed and less dynamic in Capn4-deficient cells than in rescued cells. Furthermore, Capn4-deficient cells were less adhesive than wild-type cells and they also failed to respond to mechanical stimulations by pushing or pulling the flexible substrate, or by engaging dorsal receptors to the extracellular matrix. Surprisingly, fibroblasts deficient in calpain 1 or calpain 2 upon siRNA-mediated knockdown of Capn1 or Capn2, respectively, did not show the same defects in force production or adhesion, although they also failed to respond to mechanical stimulation. Interestingly, stress fibers were aberrant and also contained fewer colocalised vinculin-containing adhesions in Capn4-deficient cells than Capn1- and Capn2-knockdown cells. Together, these results suggest that the calpain small subunit plays an important role in the production of mechanical forces and in mediating mechanosensing during fibroblast migration. Furthermore, the Capn4 gene product might perform functions secondary to, or independent of, its role as a regulatory subunit for calpain 1 and calpain 2.

Dataset Information

Disruption of the murine calpain small subunit gene, Capn4: calpain is essential for embryonic development but not for cell growth and division.

Publications

Disruption of the murine calpain small subunit gene, Capn4: calpain is essential for embryonic development but not for cell growth and division.

Similar Datasets

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