**7.1 Canonical wnt pathway**

It acts through β-catenina/Arm and specifies different cell types, controlling proliferation and apoptosis depending on the development context. It is activated in virtually all tumors. Induces stabilization and accumulation in the cytoplasm of ß-catenin and its subsequent translocation to the cell nucleus where it affects transcription of target genes [2, 3, 70, 71].


Ciliopathies: Primary Cilia and Signaling Pathways in Mammalian Development 135

 Embryo symmetry. Nodal cilia: It has been proven that nodal ciliary flow is required to generate the right/left symmetry axis. Between days 10 and 25 of embryonic development, a sophisticated biochemical reaction cascade determines that the human body will be: asymmetrical inside -with the heart on the left and liver on the right; and symmetrical outside -with two hands, two feet and the navel in the middle. Stem cells that become different body tissues enter the node (cells that direct embryo growth). The node has hundreds of cilia (nodal cilia) that guide each cell to its destination in the embryo. Nodal cilia run in subtle circular motion, creating convection currents in the fluid where the embryo is immersed (nodal flow). These currents help to carry the cells to their proper place. FoxJ1 transcription factor is the master key to the formation of

 Primary ciliary dyskinesia (PCD): is a rare autosomal recessive disease (GENE: DNAHC11, locus:7p21), characterized by abnormal ciliary structure and function. The ciliary defect is a result of absence or anomalies of dynein arms and pairs of microtubule structures responsible for movement. Patients show recurrent lung, sinus and middle ear infections. Male infertility may be present, due to immotile sperm. Female fertility is also affected, given the presence of cilia in the fallopian tubes and

fimbriae. Kartagener syndrome (50%) is associated with situs inversus [82 a 85]. Hydrocephalus appears to be specifically associated with defects in the central pair of microtubules as typified by the mouse hydin mutant, which has hydrocephalus and lacks the central pair. Ciliary motility is necessary for brain development and function;

Given the many roles of cilia in physiology and development, it is not surprising that its defects cause multiple human diseases. Perhaps cilia´s most enigmatic aspect is that only one defect involves different diseases, often with a partially overlapping set of symptoms [2]. High ranked phenotypes by: 1º the necessary ubiquitous presence in each of the cell types of the human body, and 2º the emerging role in morphogenetic signal transduction. (TABLE 2).

Retina: photo-receptors: have a primary cilium (9+0) that connects the outer segment (rhodopsin disks) to the inner segment where rhodopsin is synthesized. Molecules that detect light are synthesized in the inner segment and must be transported to the outer segment by intraciliar transport. Mutations in a gene involved in transport of these molecules needed for seeing or outer segment maintenance result in degeneration of photoreceptors leading to blindness such as in retinitis pigmentosa. Dysfunction of primary cilia due to mutations in cilia-centrosomal proteins is associated with pleiotropic disorders. The primary (or sensory) cilium of photoreceptors mediates polarized trafficking of proteins for efficient phototransduction. Retinitis pigmentosa GTPase regulator (RPGR) is a cilia-centrosomal protein mutated in >70% of X-linked RP cases and 10%-20% of simplex RP males. Accumulating evidence indicates that RPGR may facilitate the orchestration of

the "ependymal flow" is required to maintain an open aqueduct [86, 87].




**8.2 Sensory cilia dysfunction (cilium)** 



nodal cilia, which are responsible for left-right asymmetry [79 a 81].

cord. Wnt signaling is active in the mouse ventral spinal cord at the time when ventral cell types are specified. Furthermore, using an approach that stabilizes beta-catenin protein in small patches of ventral spinal cord cells at different stages, Wnt signaling activates different subsets of target genes depending on the time when Wnt signaling is amplified. Moreover, disruption of Wnt signaling results in the expansion of ventrally located progenitors. Finally, Wnt signaling interacts with Hh signaling at least in part through regulating the transcription of Gli3. Yu W. et al [72] reveal a novel mechanism by which ventral patterning is achieved through coordination of Wnt and Shh signaling.

#### **7.2 The planar cell polarity pathway (PCP)**

Sets the polarization of the cells along the plane of a tissue membrane. This pathway is important for neural tube closure and cochlear extension of the inner ear. Is involved in cell polarity, tissue and cell movement processes.

#### **7.3 WNT/CA+2 OR "Non-canonical" pathway**

Regulates cell adhesion and motility mediated by Wnt-5a, triggers intracellular Ca2+ release to activate Ca2+-sensitive enzymes such as protein kinase C (PKC ), calmodulin-dependent kinase II and Ca2+ (CaMKII) without ß-catenin pathway activation.
