The physiological roles of primary ciliary resorption and its potential as therapeutic targets

Abstract

Primary cilia are cellular antennae protruding from the surface of nearly all cell types during the G₀ phase. They control the organization and maturation of systemic tissues and organs by receiving selective signals. Ciliopathies are heritable disorders that cause dysplasia of various tissues and organs, as well as the progression of obesity. In contrast, recent studies using cultured cells have revealed that cilia were resorbed upon receiving selective proliferative stimuli, thereby reentering the cell cycle into the G₁/S phase. However, the physiological significance and molecular mechanisms of ciliary resorption were unclear, as no diseases caused by abnormal ciliary resorption had been identified in humans or experimental animals. To address this problem, we focused on the role of the cytoplasmic dynein light chain Tctex-1. We found that activating the insulin-like growth factor-1 receptor at cilia results in the phosphorylation of threonine 94 in Tctex-1 and subsequent endocytosis of the ciliary pocket membrane surrounding the ciliary basal region. This mechanism is responsible for ciliary resorption and reentry into the G₁/S phases of the cell cycle. Additionally, we found that phospho-(T94)Tctex-1 localizes to the ciliary transition zone of neural progenitor cells in the fetal cerebral cortex, where it regulates cell cycle reentry and neurogenesis. Recent reports indicate that mice with abnormal ciliary resorption develop microcephaly-like symptoms. Our study and these reports shed light on the physiological significance of ciliary resorption. Finally, this review discusses new directions in ciliary resorption research and its potential therapeutic applications.