Primary cilia in the developing and mature brain

Abstract

Primary cilia were the largely neglected nonmotile counterparts of their better-known cousin, the motile cilia. For years these nonmotile cilia were considered evolutionary remnants of little consequence to cellular function. Fast forward 10 years and we now recognize primary cilia as key integrators of extracellular ligand-based signaling and cellular polarity, which regulate neuronal cell fate, migration, differentiation, as well as a host of adult behaviors. Important future questions will focus on structure-function relationships, their roles in signaling and disease and as areas of target for treatments.

Figure 1. Neural patterning phenotypes in intraflagellar transport mutants

Axonemal and membrane components are transported by intraflagellar transport (IFT) particles (complexes B and A) along the axoneme toward the tip complex (anterograde transport) by kinesins and in the opposite direction (retrograde transport) by the motor dyneins, respectively. In wt embryos, ventral neural cell fates are specified by Shh gradient. Anterograde IFT-B mutants Ift88 or Ift172 lack cilia, Shh signaling is reduced and the neural tube is dorsalized. Retrograde IFT-A mutants like Ift139 exhibit excess Shh signaling and expanded ventral cell pools. Mutations that disrupt the kinesin Kif7 cause a partial activation of the Shh pathway, with an expansion of motor neurons that require intermediate levels of Shh. V0, V1, motor neurons, V3 and floor plate represent progressive more ventral cell types in the developing spinal cord. (Adapted from (Goetz and Anderson, 2010))

Figure 2. Primary cilia participate neural migration during cortical development via Arl13b

Arl13b is critical for the formation of the polarized radial progenitor scaffold (wildtype). Deletion of Arl13b led to a reversal in radial glial apical-basal polarity, inversion of position of reelin-producing cells, and consequently to aberrant neuronal migration, i.e. from the pial surface to the ventricular surface (arrow indicates direction).

Figure 3. Proposed roles for cilia in regulation of weight and predisposition to obesity

A. Bbs knockout or IFT88 conditional knockout mice are obese and show reduced leptin responsiveness. However, both before weight gain and after weight loss the knockouts show intact leptin responsiveness, suggesting the leptin insensitivity is secondary to obesity, and is independent of ciliary function. B. Models for the roles of ciliopathy proteins in obesity. Left: proposes leptin receptors at the cell membrane require BBS for trafficking and downstream Stat3 signaling. Right: proposes other satiety signals like NPY, signaling through its cilia-localized NPY2R GPCR receptor, requires BBS components for trafficking and modulation of cAMP levels. Alternatively, cilia may modulate satiety through pathways such as mTOR or Mchr1.