Distinct roles for Ste20-like kinase SLK in muscle function and regeneration

Abstract

BackgroundCell growth and terminal differentiation are controlled by complex signaling systems that regulate the tissue-specific expression of genes controlling cell fate and morphogenesis. We have previously reported that the Ste20-like kinase SLK is expressed in muscle tissue and is required for cell motility. However, the specific function of SLK in muscle tissue is still poorly understood.MethodsTo gain further insights into the role of SLK in differentiated muscles, we expressed a kinase-inactive SLK from the human skeletal muscle actin promoter. Transgenic muscles were surveyed for potential defects. Standard histological procedures and cardiotoxin-induced regeneration assays we used to investigate the role of SLK in myogenesis and muscle repair.ResultsHigh levels of kinase-inactive SLK in muscle tissue produced an overall decrease in SLK activity in muscle tissue, resulting in altered muscle organization, reduced litter sizes, and reduced breeding capacity. The transgenic mice did not show any differences in fiber-type distribution but displayed enhanced regeneration capacity in vivo and more robust differentiation in vitro.ConclusionsOur results show that SLK activity is required for optimal muscle development in the embryo and muscle physiology in the adult. However, reduced kinase activity during muscle repair enhances regeneration and differentiation. Together, these results suggest complex and distinct roles for SLK in muscle development and function.

Essential role for the SLK protein kinase in embryogenesis and placental tissue development

“…D). As previously reported (Zhang et al, ; Storbeck et al, ), expression was readily detectable in all muscle groups of the embryo, in addition to the cartilage, the developing bone and fetal liver (Fig. E–G).…”

“…Embryos were harvested by caesarian section at E12.5 and stained using X-gal or anti-b-galactosidase antibodies. As previously observed for endogenous SLK (Zhang et al, 2002;Storbeck et al, 2004Storbeck et al, , 2013, whole mount X-gal staining of E12.5 embryos showed high levels of SLK-LacZ fusion protein in the limb buds and forebrain regions of these embryos ( Fig. 2A).…”

“…Altering these signaling pathways can result in defects which can lead to severe embryonic defects and lethality. Previous work has shown that SLK is highly expressed within neuronal and skeletal muscle lineages of the developing embryo (Zhang et al, 2002;Storbeck et al, 2004Storbeck et al, , 2013. However, little is known about the specific function of SLK in controlling the development of these structures in vivo.…”

“…Our previous results have shown that SLK is preferentially expressed in the neuronal and skeletal muscle lineages of the developing embryos (Zhang et al, 2002;Storbeck et al, 2013). To validate this and to further characterize SLK expression in the embryo, we performed LacZ histochemistry and b-galactosidase immunohistochemistry on heterozygote embryos.…”

“…To date, the role of SLK in vivo has been investigated using transgenic approaches and tissue specific overexpression of wild‐type or kinase dead SLK (Cybulsky et al, ; Storbeck et al, ). Functional roles for SLK have been uncovered in muscle‐specific differentiation and fusion, as well as in podocyte injury (Zhang et al, ; Storbeck et al, ; Cybulsky et al, ). Here we report the generation and characterization of an SLK gene‐trapped allele.…”