br Hedgehog pathway The Hedgehog

Hedgehog pathway The Hedgehog pathway (Fig. 1) derives its name from Hh gene mutant Drosophila, which presents a spiked phenotype resembling the animal “hedgehog” [13]. The Hh proteins control embryonic development in vertebrates, where the signaling mechanisms mediated by the proteins are multiple and increasingly variable. For instance, they can act as morphogens (by mediating the morphogenesis process in a concentration dependent manner) or mitogens (by controlling cell proliferation through the mitosis process) [14]. The Hh gene has three homologues in mammals: IHh (Indian hedgehog), SHh (Sonic hedgehog) and DHh (Desert hedgehog), with Sonic hedgehog being the most studied. The IHh homologue is produced by the chondrocytes (cells of the cartilage) and is involved in controlling their differentiation with a role in regulating osteoarthritis. The transmembrane proteins PTCH1 (Patched 1) and Smo (Smoothened) respond to IHh and mediate the IHh signaling mechanism. The PTCH1 protein generally inhibits Smo in the absence of IHh by suppressing the downstream transcription factors Gli 1, 2 and 3 (Gli Zinc finger). However, in the presence of IHh the signaling mechanism is activated and the inhibition of Smo by PTCH1 is relieved. Next, the expression of Gli transcription factors is enhanced, being further translocated within the nucleus where they enhance the transcription of downstream target genes (Fig. 1) [15]. Regulatory mechanisms can also be found at the Gli transcription factor level, where Gli2 and Gli3 can be found in active or inactive forms. Where Hh is absent, Gli3 is cleaved through proteolytic mechanisms into the Gli3R (Gli3 repressor form), where Gli2 is further degraded. When Hh is expressed, the cleavage of Gli2 is blocked and can be N-terminally truncated to generate an inactive form (Gli2A) [16]. The SHh pathway (SHh is named after Sega’s jump ‘n’ run character) mainly controls the growth and development of the Safingol and is also involved in mechanisms related to the central nervous system. This pathway is mediated by the signaling molecule SHh, which mediates the expression of transcription factors depending on its deposition in the neural tube. Similar to the IHh pathway, the expression of SHh, removes the inhibition of PTCH1 on Smo and enhances the expression of Gli transcription factors (Fig. 1) [17]. The activity of SHh as a morphogen is concentration dependent, where the signaling is specifically directed dependent on the concentration of the SHh protein: for instance ventral neuron, motor neuron and floor plate cell development takes place at low, high and very high concentrations respectively [18]. On the other hand, the DHh pathway mediated by the DHh protein (which is expressed in the testis) controls the spermatogenesis process by maintaining the male germ line cell. The DHh pathway also operates through PTCH1 and Smo protein regulation (Fig. 1) [19]. The PTCH1 mediator has two additional homologues PTCH2 and HHIP1 (HH-interacting protein-1), with all three proteins playing central roles in mediating the Hh ligand signaling which occurs during the development of the embryo [20]. The Smo protein is a nodal point within the Hh signaling pathway, since it mediates the response associated with the Hh ligand. While this integral membrane protein has structural similarities with the GPCR (G-protein coupled receptors), there is little evidence to indicate a direct coupling with GPCR. In Drosophila the Smo protein accumulates in the cell membrane at the moment of Hh activation, while in vertebrates the protein gets internalized after activation of the pathway [21]. There are many essential proteins which directly phosphorylate Smo, activating the protein and allowing for initiation of the Hh pathway, such as CK1 (Casein kinase 1) and Grk2 (G‐protein‐coupled receptor kinase 2) [22]. Since the Hh signaling pathway is vital for a heterogeneous range of developmental processes, different transcription factors act in coordination to regulate the expression of said Hh protein. If any mutation occurs in these transcription factors, this will affect the expression of Hh proteins and result in developmental related conditions such as epilepsy, tibial hypoplasia, polydactyly and X-linked lissencephaly, neurological disorders and cancer [23].