A Ser75-to-Asp phospho-mimicking mutation in Src accelerates ageing-related loss of retinal ganglion cells in mice

Sci Rep. 2017 Dec 1;7(1):16779. doi: 10.1038/s41598-017-16872-7.

Abstract

Src knockout mice show no detectable abnormalities in central nervous system (CNS) post-mitotic neurons, likely reflecting functional compensation by other Src family kinases. Cdk1- or Cdk5-dependent Ser75 phosphorylation in the amino-terminal Unique domain of Src, which shares no homology with other Src family kinases, regulates the stability of active Src. To clarify the roles of Src Ser75 phosphorylation in CNS neurons, we established two types of mutant mice with mutations in Src: phospho-mimicking Ser75Asp (SD) and non-phosphorylatable Ser75Ala (SA). In ageing SD/SD mice, retinal ganglion cell (RGC) number in whole retinas was significantly lower than that in young SD/SD mice in the absence of inflammation and elevated intraocular pressure, resembling the pathogenesis of progressive optic neuropathy. By contrast, SA/SA mice and wild-type (WT) mice exhibited no age-related RGC loss. The age-related retinal RGC number reduction was greater in the peripheral rather than the mid-peripheral region of the retina in SD/SD mice. Furthermore, Rho-associated kinase activity in whole retinas of ageing SD/SD mice was significantly higher than that in young SD/SD mice. These results suggest that Src regulates RGC survival during ageing in a manner that depends on Ser75 phosphorylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / genetics*
  • Aging / pathology
  • Amino Acid Substitution*
  • Animals
  • Apoptosis
  • Asparagine / genetics
  • Cell Count
  • Cell Survival
  • Mice
  • Mice, Knockout
  • Optic Nerve Diseases / genetics
  • Optic Nerve Diseases / pathology
  • Phosphorylation
  • Proto-Oncogene Proteins pp60(c-src) / chemistry
  • Proto-Oncogene Proteins pp60(c-src) / genetics*
  • Proto-Oncogene Proteins pp60(c-src) / metabolism
  • Retinal Ganglion Cells / cytology*
  • Retinal Ganglion Cells / metabolism
  • Retinal Ganglion Cells / pathology
  • Serine / genetics*

Substances

  • Serine
  • Asparagine
  • Proto-Oncogene Proteins pp60(c-src)