Post-transcriptional and Post-translational Modifications of Primary Cilia: How to Fine Tune Your Neuronal Antenna

Abstract

Primary cilia direct cellular signaling events during brain development and neuronal differentiation. The primary cilium is a dynamic organelle formed in a multistep process termed ciliogenesis that is tightly coordinated with the cell cycle. Genetic alterations, such as ciliary gene mutations, and epigenetic alterations, such as post-translational modifications and RNA processing of cilia related factors, give rise to human neuronal disorders and brain tumors such as glioblastoma and medulloblastoma. This review discusses the important role of genetics/epigenetics, as well as RNA processing and post-translational modifications in primary cilia function during brain development and cancer formation. We summarize mouse and human studies of ciliogenesis and primary cilia activity in the brain, and detail how cilia maintain neuronal progenitor populations and coordinate neuronal differentiation during development, as well as how cilia control different signaling pathways such as WNT, Sonic Hedgehog (SHH) and PDGF that are critical for neurogenesis. Moreover, we describe how post-translational modifications alter cilia formation and activity during development and carcinogenesis, and the impact of missplicing of ciliary genes leading to ciliopathies and cell cycle alterations. Finally, cilia genetic and epigenetic studies bring to light cellular and molecular mechanisms that underlie neurodevelopmental disorders and brain tumors.

Keywords: RNA splicing; brain tumors; epigenetics; neurons; primary cilia.

FIGURE 1

Primary cilia in brain development, maturation, and disease. Ciliogenesis is tightly coordinated with the cell cycle as primary cilia assemble and disassemble during the different phases functioning as a barrier to cell cycle progression. Whereas resting and differentiated cells form a cilium, proliferating cells such as stem cells and progenitor cells disassemble their primary cilia prior to cell division. Stem cell proliferation is important for stem cell self-renewal, maintenance of the progenitor pool and subsequent lineage commitment and differentiation. Many post-transcriptional and post-translational modifications take place in the cilium modulating its formation, stability and activity as depicted in the figure. Therefore, cilia defects and absence affect proliferation and differentiation of neural progenitors leading to developmental diseases and cancer such as Glioblastoma and Medulloblastoma. Cilia disassembly defects cause elongation delaying cell cycle re-entry leading to premature differentiation of NPCs and reducing the pool of progenitors and ultimately leading to microcephaly. Moreover, the ciliary status of neuronal cells from patients with neurodevelopmental and neurodegenerative diseases is yet to be determined. Thus, cilia function is essential for stem cell maintenance, neural development and neural function in health and disease.