The PATCHED/Sonic Hedgehog signalling pathway in superficial bladder cancer

Superficial bladder cancer shows a high frequency of total or partial chromosome 9 losses. Loss of heterozygosity at position 9q22.3 is one of the most frequent and is associated with highly recurrent tumours. The PATCHED gene, ortholog of a gene first described in the drosophila as a segment polarity gene, is located at 9q22.3. It is a member of a signal transduction pathway and a tumour suppressor gene (TSG), involved in basal cell carcinoma. We propose PATCHED as a TSG candidate in superficial bladder cancer.     

Patching the gaps in Hedgehog signalling

The Hedgehog (Hh) pathway plays central roles in animal development and stem-cell function. Defects in Hh signalling lead to birth defects and cancer in humans. The first and often genetically damaged step in this pathway is the interaction between two membrane proteins - Patched (Ptc), encoded by a tumour suppressor gene, and Smoothened (Smo), encoded by a proto-oncogene. Recent work linking Hh signalling to sterol metabolites and protein-trafficking events at the primary cilium promises to shed light on the biochemical basis of how Patched inhibits Smoothened, and to provide new avenues for cancer treatment.     

The adventures of Sonic Hedgehog in development and repair. I. Hedgehog signaling in gastrointestinal development and disease

Hedgehog (Hh) proteins are members of a family of secreted signaling factors that orchestrate the development of many organs and tissues including those of the gastrointestinal (GI) tract. The requirement for Hh activity is not limited to early development but underlies the homeostasis of a number of tissues, and abnormal activity of the Hh pathway is associated with several GI malignancies. Understanding the roles and mechanisms of action of Hh signaling both in development and postnatally should thus give novel insights into potential treatments for these diseases. Here we focus on the Hh signaling pathway and its role in GI tract development and maintenance and consider the diseases resulting from aberrant Hh activity.     

Sonic hedgehog controls stem cell behavior in the postnatal and adult brain

Sonic hedgehog (Shh) signaling controls many aspects of ontogeny, orchestrating congruent growth and patterning. During brain development, Shh regulates early ventral patterning while later on it is critical for the regulation of precursor proliferation in the dorsal brain, namely in the neocortex, tectum and cerebellum. We have recently shown that Shh also controls the behavior of cells with stem cell properties in the mouse embryonic neocortex, and additional studies have implicated it in the control of cell proliferation in the adult ventral forebrain and in the hippocampus. However, it remains unclear whether it regulates adult stem cell lineages in an equivalent manner. Similarly, it is not known which cells respond to Shh signaling in stem cell niches. Here we demonstrate that Shh is required for cell proliferation in the mouse forebrain's subventricular zone (SVZ) stem cell niche and for the production of new olfactory interneurons in vivo. We identify two populations of Gli1+ Shh signaling responding cells: GFAP+ SVZ stem cells and GFAP- precursors. Consistently, we show that Shh regulates the self-renewal of neurosphere-forming stem cells and that it modulates proliferation of SVZ lineages by acting as a mitogen in cooperation with epidermal growth factor (EGF). Together, our data demonstrate a critical and conserved role of Shh signaling in the regulation of stem cell lineages in the adult mammalian brain, highlight the subventricular stem cell astrocytes and their more abundant derived precursors as in vivo targets of Shh signaling, and demonstrate the requirement for Shh signaling in postnatal and adult neurogenesis.     

Role of Sonic Hedgehog Signaling in Oligodendrocyte Differentiation

During development, the secreted molecule Sonic Hedgehog (Shh) is required for lineage specification and proliferation of oligodendrocyte progenitors (OLPs), which are the glia cells responsible for the myelination of axons in the central nervous system (CNS). Shh signaling has been implicated in controlling both the generation of oligodendrocytes (OLGs) during embryonic development and their production in adulthood. Although, some evidence points to a role of Shh signaling in OLG development, its involvement in OLG differentiation remains to be fully determined. The objective of this study was to assess whether Shh signaling is involved in OLG differentiation after neural stem cell commitment to the OLG lineage. To address these questions, we manipulated Shh signaling using cyclopamine, a potent inhibitor of Shh signaling activator Smoothened (Smo), alone or combined with the agonist SAG in OLG primary cultures and assessed expression of myelin-specific markers. We found that inactivation of Shh signaling caused a dose-dependent decrease in myelin basic protein (MBP) and myelin associated glycoprotein (MAG) in differentiating OLGs. Co-treatment of the cells with SAG reversed the inhibitory effect of cyclopamine on both myelin-specific protein levels and morphological changes associated with it. Further experiments are required to elucidate the molecular mechanism by which Shh signaling regulates OLG differentiation.     

Sonic Hedgehog在味乳头发育过程中的作用

Shh是一种作用于脊椎动物细胞分化和组织诱导的信号分子,它通过跨膜蛋白Ptc受体和信号转录因子Glil参与信号转导机制。从胚胎期（E12）到成年,Shh信号在鼠舌味乳头中的表达都非常广泛。在味乳头最初发育阶段,Shh信号的作用包括调节上皮和间质细胞的交互作用、控制乳头形成和成型、限定乳头的分布模式、决定细胞分化的命运等,破坏Shh信号会导致菌状数量增多、面积增大以及乳头分布区域更广。     

Cytoglobin is a stress-responsive hemoprotein expressed in the developing and adult brain.

Cytoglobin (Cygb) is a novel tissue hemoprotein relatively similar to myoglobin (Mb). Because Cygb shares several structural features with Mb, we hypothesized that Cygb functions in the modulation of oxygen and nitric oxide metabolism or in scavenging free radicals within a cell. In the present study we examined the spatial and temporal expression pattern of Cygb during murine embryogenesis. Using in situ hybridization, RT-PCR, and Northern blot analyses, limited Cygb expression was observed during embryogenesis compared with Mb expression. Cygb expression was primarily restricted to the central nervous system and neural crest derivatives during the latter stages of development. In the adult mouse, Cygb is expressed in distinct regions of the brain as compared with neuroglobin (Ngb), another globin protein, and these regions are responsive to oxidative stress (i.e., hippocampus, thalamus, and hypothalamus). In contrast to Ngb, Cygb expression in the brain is induced in response to chronic hypoxia (10% oxygen). These results support the hypothesis that Cygb is an oxygen-responsive tissue hemoglobin expressed in distinct regions of thenormoxic and hypoxic brain and may play a key role in the response of the brain to ahypoxic insult.     

p63 overexpression induces the expression of Sonic Hedgehog

p63 and p73 are members of the p53 protein family and have been shown to play an important role in cell death, development, and tumorigenesis. In particular, p63 has been shown to be involved in the maintenance of epidermal stem cells and in the stratification of the epidermis. Sonic Hedgehog (Shh) is a morphogen that has also been implicated to play a role in epithelial stem cell proliferation and in the development of organs. Recently, Shh has also been shown to play an important role in the progression of a variety of cancers. In this report, we show that p63 and p73 but not p53 overexpression induces Shh expression. In particular, p63gamma and p63beta (both TA and DeltaN isoforms) and TAp73beta isoform induce Shh. Expression of Shh was found to be significantly reduced in mouse embryo fibroblasts obtained from p63-/- mice. The naturally occurring p63 mutant TAp63gamma(R279H) and the tumor suppressor protein p14(ARF) inhibited the TAp63gamma-mediated transactivation of Shh. The region -228 to -102 bp of Shh promoter was found to be responsive to TAp63gamma-induced transactivation and TAp63gamma binds to regions within the Shh promoter in vivo. The results presented in this study implicate p63 in the regulation of the Shh signaling pathway.     

Patched/Sonic Hedgehog pathway and basal cell carcinoma

The recent discovery of the role of the Patched Sonic Hedgehog pathway in the physiopathogeny of BCC (basocellular carcinoma) and Gorlin's syndrome has greatly improved our knowledge on the mechanism of development of these tumors. For the first time, murine models have been developed allowing to further understand other molecular events implicated in such tumors as well as providing in vivo models to search for new curative or preventive therapeutical strategies which would be helpful to control CBC multiple forms, that are often disabling.     

Sonic hedgehog signalling in T-cell development and activation

The production of mature functional T cells in the thymus requires signals from the thymic epithelium. Here, we review recent experiments showing that one way in which the epithelium controls the production of mature T cells is by the secretion of sonic hedgehog (SHH). We consider the increasing evidence that SHH-induced signalling is not only important for the differentiation and proliferation of early thymocyte progenitors, but also for modulating T-cell receptor signalling during repertoire selection, with implications for positive selection, CD4 versus CD8 lineage commitment, and clonal deletion of autoreactive cells. We also review the influence of hedgehog signalling in peripheral T-cell activation.     

O-GlcNAc cycling in the developing,adult and geriatric brain

Hundreds of proteins in the nervous system are modified by the monosaccharide O-GlcNAc. A single protein is often O-GlcNAcylated on several amino acids and the modification of a single site can play a crucial role for the function of the protein. Despite its complexity, only two enzymes add and remove O-GlcNAc from proteins, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). Global and local regulation of these enzymes make it possible for O-GlcNAc to coordinate multiple cellular functions at the same time as regulating specific pathways independently from each other. If O-GlcNAcylation is disrupted, metabolic disorder or intellectual disability may ensue, depending on what neurons are affected. O-GlcNAc's promise as a clinical target for developing drugs against neurodegenerative diseases has been recognized for many years. Recent literature puts O-GlcNAc in the forefront among mechanisms that can help us better understand how neuronal circuits integrate diverse incoming stimuli such as fluctuations in nutrient supply, metabolic hormones, neuronal activity and cellular stress. Here the functions of O-GlcNAc in the nervous system are reviewed.     

Choroid plexus trophic factors in the developing and adult brain

The choroid plexus (CP), localized in brain ventricles, is the major source of cerebrospinal fluid (CSF) and participates in the blood-CSF barrier. It is essential for brain immunosurveillance and the clearance of toxics, and for brain development and activity. Indeed, the CP secretes a large variety of trophic factors in the CSF that impact the entire brain. These factors are mainly implicated in neurogenesis, but also in the maintenance of brain functions and the vasculature. In this mini-review, we provide an overview of the various trophic factors secreted by the CP in the CSF, and describe their roles in the developing, adult and diseased brain.     

Palmitoylation of Hedgehog proteins by Hedgehog acyltransferase: roles in signalling and disease

Hedgehog acyltransferase (Hhat), a member of the membrane-bound O-acyltransferase (MBOAT) family, catalyses the covalent attachment of palmitate to the N-terminus of Hedgehog proteins. Palmitoylation is a post-translational modification essential for Hedgehog signalling. This review explores the mechanisms involved in Hhat acyltransferase enzymatic activity, similarities and differences between Hhat and other MBOAT enzymes, and the role of palmitoylation in Hedgehog signalling. In vitro and cell-based assays for Hhat activity have been developed, and residues within Hhat and Hedgehog essential for palmitoylation have been identified. In cells, Hhat promotes the transfer of palmitoyl-CoA from the cytoplasmic to the luminal side of the endoplasmic reticulum membrane, where Shh palmitoylation occurs. Palmitoylation is required for efficient delivery of secreted Hedgehog to its receptor Patched1, as well as for the deactivation of Patched1, which initiates the downstream Hedgehog signalling pathway. While Hhat loss is lethal during embryogenesis, mutations in Hhat have been linked to disease states or abnormalities in mice and humans. In adults, aberrant re-expression of Hedgehog ligands promotes tumorigenesis in an Hhat-dependent manner in a variety of different cancers, including pancreatic, breast and lung. Targeting hedgehog palmitoylation by inhibition of Hhat is thus a promising, potential intervention in human disease.     

Hedgehog signalling: off the shelf modulation

Many cell signalling pathways are modulated in important ways by general cellular machineries, such as those mediating protein degradation and translocation. Two recent studies have revealed roles for such mechanisms in the Hedgehog signalling pathway in Drosophila.     

Control of neuronal precursor proliferation in the cerebellum by Sonic Hedgehog

Cerebellar granule cells are the most abundant type of neuron in the brain, but the molecular mechanisms that control their generation are incompletely understood. We show that Sonic hedgehog (Shh), which is made by Purkinje cells, regulates the division of granule cell precursors (GCPs). Treatment of GCPs with Shh prevents differentiation and induces a potent, long-lasting proliferative response. This response can be inhibited by basic fibroblast growth factor or by activation of protein kinase A. Blocking Shh function in vivo dramatically reduces GCP proliferation. These findings provide insight into the mechanisms of normal growth and tumorigenesis in the cerebellum.