Negative regulation of ciliary length by ciliary male germ cell-associated kinase (Mak) is required for retinal photoreceptor survival

Proc Natl Acad Sci U S A. 2010 Dec 28;107(52):22671-6. doi: 10.1073/pnas.1009437108. Epub 2010 Dec 8.

Abstract

Cilia function as cell sensors in many organs, and their disorders are referred to as "ciliopathies." Although ciliary components and transport machinery have been well studied, regulatory mechanisms of ciliary formation and maintenance are poorly understood. Here we show that male germ cell-associated kinase (Mak) regulates retinal photoreceptor ciliary length and subcompartmentalization. Mak was localized both in the connecting cilia and outer-segment axonemes of photoreceptor cells. In the Mak-null retina, photoreceptors exhibit elongated cilia and progressive degeneration. We observed accumulation of intraflagellar transport 88 (IFT88) and IFT57, expansion of kinesin family member 3A (Kif3a), and acetylated α-tubulin signals in the Mak-null photoreceptor cilia. We found abnormal rhodopsin accumulation in the Mak-null photoreceptor cell bodies at postnatal day 14. In addition, overexpression of retinitis pigmentosa 1 (RP1), a microtubule-associated protein localized in outer-segment axonemes, induced ciliary elongation, and Mak coexpression rescued excessive ciliary elongation by RP1. The RP1 N-terminal portion induces ciliary elongation and increased intensity of acetylated α-tubulin labeling in the cells and is phosphorylated by Mak. These results suggest that Mak is essential for the regulation of ciliary length and is required for the long-term survival of photoreceptors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Blotting, Western
  • Female
  • Gene Expression Regulation, Developmental
  • HEK293 Cells
  • Humans
  • In Situ Hybridization
  • Male
  • Mice
  • Mice, Knockout
  • Microscopy, Electron, Transmission
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism
  • Models, Biological
  • Molecular Sequence Data
  • NIH 3T3 Cells
  • Phosphorylation
  • Photoreceptor Connecting Cilium / metabolism*
  • Photoreceptor Connecting Cilium / ultrastructure
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Retina / embryology
  • Retina / growth & development
  • Retina / metabolism*
  • Retinal Photoreceptor Cell Outer Segment / metabolism*
  • Retinal Photoreceptor Cell Outer Segment / ultrastructure
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sequence Homology, Amino Acid
  • Time Factors

Substances

  • Microtubule-Associated Proteins
  • RP1 protein, mouse
  • Protein Serine-Threonine Kinases
  • Mak protein, mouse