Roles of Primary Cilia in the Developing Brain

Abstract

Essential to development, primary cilia are microtubule-based cellular organelles that protrude from the surface of cells. Acting as cellular antenna, primary cilia play central roles in transducing or regulating several signaling pathways, including Sonic hedgehog (Shh) and Wnt signaling. Defects in primary cilia contribute to a group of syndromic disorders known as "ciliopathies" and can adversely affect development of the brain and other essential organs, including the kidneys, eyes, and liver. The molecular mechanisms of how defective primary cilia contribute to neurological defects, however, remain poorly understood. In this mini review, we summarize recent advances in understanding of the interactions between primary cilia and signaling pathways essential to cellular homeostasis and brain development.

Keywords: FMCD; MTOR; Wnt; autophagy; ciliopathy; primary cilia.

FIGURE 1

Primary cilia and signal transduction. (A) Structure of primary cilium. Microtubules extend from the centriole constituting the basal body and form the axoneme. The surrounding membrane is called the ciliary membrane, distinct from other membranes. Unlike motile cilium with a 9+2 structure, primary cilium has a 9+0 structure. Only ciliary proteins are allowed to access the cilium, and the transition zone performs the filtering function. (B) In the absence of Shh, Patched (Ptch) inhibits the translocation of Smoothened (Smo), a membrane G protein-coupled receptor (GPCR)-like protein. Suppressor of Fused (SUFU) in the tip of the cilium represses Gli, causing Gli to be present in an inactive form. In the presence of Shh, Shh binds to Ptch, making it no longer able to suppress Smo. Smo, relieved from suppression, translocates into the cilium and represses SUFU. Gli is then converted to its active form and translocates from the cilium to the nucleus and transcribes target genes. (C) Primary cilia in Wnt signaling. In the absence of Wnt ligand, the β-catenin destruction complex, comprising glycogen synthase kinase 3β (GSK3β), adenomatous polyposis coli (APC), and Axin, phosphorylates β-catenin, leading to its proteasomal degradation, which occurs near the basal body. Wnt signaling is activated by binding extracellular Wnt ligand to the membrane-bounded receptor family, frizzled and low-density lipoprotein receptor-related protein (LRP). Then, the β-catenin destruction complex is destabilized by anchoring Axin to the plasma membrane through Dishevelled (Dvl), which leads to stabilization and nuclear localization of β-catenin for transcriptional activation of target genes under T-cell factor/lymphoid enhancer-binding factor (TCF/LEF) promoters (van Amerongen and Nusse, 2009). Inversin, for which ciliary localization has been reported, mediates proteasomal degradation of Dvl to regulate Wnt signaling.

FIGURE 2

Defective ciliogenesis due to brain somatic mutations in MTOR accounts for cortical dyslamination in FMCDs. (A) Representative brain MRIs of patients with FMCDs, including hemimegalencephaly (HME) and focal cortical dysplasia (FCD) type II. Arrows indicate the affected region of the brain. Adapted from Park et al. (2018), with permission. (B) Immunostaining for Arl13b, a marker for primary cilia, and NeuN, a marker for neurons, with DAPI co-staining in brain tissue from FMCD patients. While primary cilium normally forms at each neuron in brain tissue from non-FMCD, FMCD patients with brain somatic mutations in MTOR exhibit defective neuronal ciliogenesis. Scale bars, 30 μm. Adapted from Park et al. (2018), with permission. (C) Autophagic degradation of the centriolar satellite pool of OFD1 induces primary ciliogenesis. However, brain somatic activating mutation in MTOR, which blocks autophagy, disrupts ciliogenesis in brain tissues with FMCDs. (D) Cortical dyslamination with ciliary defective dysmorphic neurons in the cerebral cortex of a FMCD patient. Somatic activating mutations in MTOR, causative for FMCDs, disrupt neuronal ciliogenesis through blockage of autophagy, resulting in cortical dyslamination.