**3. Motility: Agents of cellular movement**

Cilia also generate mucus flow and cerebrospinal fluid [12], and can act as mechanosensors and flow meters. Many studies have demonstrated motility as one of the main functions of cilia, and its impairment may cause severe phenotypes such as decreased ciliary beat frequency in the respiratory epithelium [13]. Ciliary motility is also required for brain development and function. The ependymal motile 9+2 cilia are responsible for ependymal

Ciliopathies: Primary Cilia and Signaling Pathways in Mammalian Development 129

mammalian cells, RNAi knockdown of a protein important for PCM organization, pericentrin, inhibits ciliogenesis and reduces the abundance of IFT components near the centrioles [21]. Mutations in a *Drosophila* pericentrin-like homolog also cause malformations in sensory neuron cilia and sperm, indicating that the pericentrin-mediated interaction between centrosomal and IFT proteins is evolutionarily conserved [22]. Misregulation of cell cycle control is at the basis of oncogenesis. The cancer-promoting proteins Aurora A and HEF1/NEDD9/CAS-L play a role in primary cilium stabilization. Loss of cilia in cancer may

contribute to the insensitivity of cancer cells to environmental repressive signals [23].

intraflagellar transport (IFT) along the axonemal microtubule doublets [24].


During ciliogenesis, cilia elongate from the basal body by the addition of new axonemal subunits to the distal tip. As protein synthesis does not occur in cilia, axonemal and membrane components are conveyed in non-membrane-bound macromolecular particles by

The proteins are transported as convoys, bringing together several proteins called *"IFT* 

At the tip of the cilium there is a particular structure where there is a change in intraciliar transport direction [27 a 29]. Large IFT particles move between the axoneme microtubule doublets and ciliary membrane, transported by specific Golgi vesicles directed toward the ciliary pore complex using cytoplasmic dynein. These vesicles exocyst at the base of the cilium, where kinesin II transports the particles up to the tip. By shortening or recycling of the cilium, the IFT descend to the base by means of dynein 2 for recycling [31]. IFT play a key role in ciliogenesis, taking axoneme components synthesized in the cytoplasm to the tip

Intraciliar or intraflagellar transport is responsible for cilia growth, for renewal of its components and for the particular formation of the cilium membrane that distinguishes it

The process and transfer of information signals to the cell are mediated by specialized

Cationic channels compounds by *polycystin proteins Pc1 and Pc2* in the ciliary membrane

 Several microtubule-associated protein complexes that include proteins associated with nephronophthisis [NPHP, investment (Invs)], and with Bardet-Biedl syndrome (BBS). Hedgehog proteins (Hh) are a group of signaling proteins generating extracellular ligands that play an important role in regulating cell differentiation. In humans, there are three known Hedgehog proteins: Sonic Hh (Shh), Indian Hh and Desert Hh. When these ligands bind to various specific receptors, they trigger a signaling cascade resulting in activation of transcription factors of the Gli family that regulate the transcription of effector genes. The Hh receptors in vertebrates are the integral membrane "Patched" proteins Ptc1 and Ptc2 .

*Platelet-derived growth factor receptors (Pdgfr*), sensitive to extracellular ligands.

**5. Intraflagellar transport protein system (IFT)** 

*particles".* IFT have 2 transport routes [25, 26]:

from the rest of the plasma membrane [30].

are sensitive to mechanical stimuli.

Smoothened Receptors (Smo) [32]: The nodal point of life.

of the cilium.

proteins [3]:

**6. Hedgehog pathway** 

flow; ciliary motility loss leads to reduced fluid flow in brain ventricles, resulting in hydrocephalus [14, 15, 16]

Motility is the main feature of the unique 9+0 primary cilium at the embryonic node, which is essential for correct embryonic development. Impairment of these cilia result in embryos showing randomized left-right asymmetry and randomized turning and heart looping [17
