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Appropriate axonal growth and connectivity are essential for functional wiring of the brain. Joubert syndrome-related disorders (JSRD), a group of ciliopathies in which mutations disrupt primary cilia function, are characterized by axonal tract malformations. However, little is known about how cilia-driven signaling regulates axonal growth and connectivity. We demonstrate that the deletion of related JSRD genes, Arl13b and Inpp5e, in projection neurons leads to de-fasciculated and misoriented axonal tracts. Arl13b deletion disrupts the function of its downstream effector, Inpp5e, and deregulates ciliary-PI3K/AKT signaling. Chemogenetic activation of ciliary GPCR signaling and cilia-specific optogenetic modulation of downstream second messenger cascades (PI3K, AKT, and AC3) commonly regulated by ciliary signaling receptors induce rapid changes in axonal dynamics. Further, Arl13b deletion leads to changes in transcriptional landscape associated with dysregulated PI3K/AKT signaling. These data suggest that ciliary signaling acts to modulate axonal connectivity and that impaired primary cilia signaling underlies axonal tract defects in JSRD.
This article was published in the following journal.
Name: Developmental cell
Primary cilia function as cellular signaling hubs, integrating multiple signaling pathways. Patients with the ciliopathy Joubert syndrome have been suggested to have axonal tract defects. In this issu...
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Methods used to label and follow the course of NEURAL PATHWAYS by AXONAL TRANSPORT of injected NEURONAL TRACT-TRACERS.
A specific complex of WNT SIGNALING PATHWAY proteins that mediates the phosphorylation-dependent destruction of cytosolic BETA-CATENIN. The complex is disrupted by cell surface binding of WNT PROTEINS, which allows beta-catenin levels to rise to the point where they migrate to the CELL NUCLEUS and activate transcription.
Members of the transforming growth factor superfamily that play a role in pattern formation and differentiation during the pregastrulation and GASTRULATION stages of chordate development. Several nodal signaling ligands are specifically involved in the genesis of left-right asymmetry during development. The protein group is named after a critical region of the vertebrate embryo PRIMITIVE STREAK referred to as HENSEN'S NODE.
A class of ciliate protozoa. Characteristics include the presence of a well developed oral apparatus and oral cilia being clearly distinct from somatic cilia.
Populations of thin, motile processes found covering the surface of ciliates (CILIOPHORA) or the free surface of the cells making up ciliated EPITHELIUM. Each cilium arises from a basic granule in the superficial layer of CYTOPLASM. The movement of cilia propels ciliates through the liquid in which they live. The movement of cilia on a ciliated epithelium serves to propel a surface layer of mucus or fluid. (King & Stansfield, A Dictionary of Genetics, 4th ed)