**6.3 Oncology and carcinogenicity**

132 Neuroimaging for Clinicians – Combining Research and Practice

and expression of antiapoptotic genes. Moreover, the neocortex, cerebellum and tectum growth also depend on the mitogenic activity of Shh [51 a 55]. Recently, it has been attributed a role in axonal growth [56], and in maintaining stem cell niches in the adult.

In adults, the Hh signal is involved in maintaining stem cell and tissue homeostasis. In neurogenesis, the brain's mature CM receives signals to divide and differentiate into neurons. The primary cilium plays a key role in the CM receiving orders to divide by the

Neural stem cells (NSCs) are present in the mammalian brain from embryo to adult. It has been shown that these cells are a significant source of new neurons, and promise to be the origin of a new central nervous system restorative therapy: Hedgehog (Hh) signaling is involved in a wide range of important biological activities. Within the vertebrate central nervous system, Sonic Hedgehog (Shh) can act as a morphogen or mitogen that regulates the patterning, proliferation, and survival of neural stem cells (NSCs). However, its role in embryonic stem cell (ESC) neurogenesis has not been explored in detail. Hh signaling is required for ESC neurogenesis; in order to elucidate the underlying mechanism, Cai C. et al [57] utilized the Sox1-GFP ESC line, which has a green fluorescent protein (GFP) reporter under the control of the Sox1 gene promoter, providing an easy means of detecting NSCs in live cell culture. That ESC differentiation in adherent culture follows the ESC--> primitive ectoderm --> neurectoderm transitions observed in vivo. Selective death of the Sox1-GFPnegative cells contributes to the enrichment of Sox1-GFP-positive NSCs. Interestingly, Shh is expressed exclusively by the NSCs themselves and elicits distinct downstream gene expression in Sox1-GFP-positive and -negative cells. Suppression of Hh signaling by antagonist treatment leads to different responses from these two populations as well: increased apoptosis in Sox1- GFP-positive NSCs and decreased proliferation in Sox1-GFP-negative primitive ectoderm cells. Hedgehog agonist treatment, in contrast, inhibits apoptosis and promotes proliferation of Sox1-GFP-positive NSCs. These results suggest that Hh acts as a mitogen and survival factor during early ESC neurogenesis, and evidence is presented to support a novel autocrine

**6.2 Stem cell proliferation and differentiation: neurogenesis** 

Degenerative defects:

cord [58].

uptake of cell growth factors through the route called "Sonic hedgehog".

mechanism for Hh-mediated effects on NSC survival and proliferation.

involved in maintaining stem cell numbers.

An intravenous Hh agonist at doses that upregulate spinal cord Gli1 transcription also increases the population of neural precursor cells after spinal cord injury in adult rats. These data support previous findings based on injections of Shh protein directly into the spinal

A common feature of embryonic and adult NSCs is that they have a primary cilium emerging from a mother centriole, and through its receptors Sonic Hedgehog (Shh) is involved in cell specification and neurogenesis with neural progenitors´ expansion in brain development [59]. Shh is active in some groups of cells in mature organs which seem to be

In mammalian telencephalon, two postnatal neurogenesis areas are known: the hippocampus dentate gyrus and the telencephalic ventricles´ subventricular zone. Quiescent cells express low levels of Gli1, a marker of responding Shh cells, but the Shh/Gli pathway is activated to regulate the generation of new neurons [60]. The Shh signaling cascade is also involved in the

maintenance of other types of adult stem cells such as hematopoietic cells [61].

Recently, many vertebrate-specific components have been identified that act between the GOS and Gli. These include intraflagellar transport proteins which link vertebrate Hh signaling to cilia. Because abnormal Hh signaling can cause birth defects and cancer, these vertebrate-specific components may play a role in human health. Hh signaling has been involved in development of several human cancers including small cell lung carcinoma, medulloblastoma, basal cell carcinomas, digestive tract (pancreas) tumors, brain, prostate, skin, etc. [62 a 67].

PTC has been considered a tumor suppressor gene: Ptc inhibits the signaling pathway, so the loss of activity results in activation of the Shh pathway.

Many oncogenic factors may converge on Gli activity to promote tumor progression, thus pointing towards the Hh signaling cascade as a phenomenon to be considered in potential treatments for many different types of cancer. For example, Gorlin syndrome or nevoid basal cell carcinoma syndrome is caused by a disorder of chromosome 9 (q22.3 and q31) and 1 (p32), leading to mutations in the PTCH tumor suppressor gene, a human homologue of *Drosophila melanogaster patched* gene. The PTCH gene encodes the signal's Sonic Hedgehog (Shh) transmembrane protein receptor, a regulatory molecule in embryogenesis and carcinogenesis [68].
