Book Title:
Hedgehog-Gli Signaling in Human Disease
Editor: Ruiz i Altaba , Ariel
ISBN: N / A

Chapter:
How the Hedgehog Outfoxed the Crab: Interference with HEDGEHOG-GLI

Abstract:
The enormous success of the last two decades in molecular embryology and developmental genetics have afforded fresh views on old problems. For instance, from a developmental point of view there is an alternative way to think about solid cancers that contrast with the single cell focus derived from molecular and cell biology and their emphasis on the cell cycle and the concepts of transformation and oncogene. One can consider cancers as diseases of patterning affecting stem cell lineages or properties. Within this framework, the funnel hypothesis1 suggests that the multiple ways to induce a given type of tumor in the mouse and the many functional mutations identified in a given tumor in humans lead to the activation of a single or few events in the cell that affect its position and identity. A one to one relationship between phenotype and final molecular mechanism with some redundancy is proposed for cancer, much as in embryonic development. Moreover, the ability of pathologists to recognize consistent morphologies in tumors and to give appropriate diagnoses is explained by the action of consistent paradevelopmental programs.1 Concepts like cell competence, specification, niche, developmental history and positional information thus become central to understand, and hopefully treat, cancer. Indeed, under this light, understanding cancer becomes necessary in order to have a complete view of developmental potential.


Chapter:
Splitting Hairs: Dissecting the Roles of Gli Activator and Repressor Functions during Epidermal Development and Disease
Pleasantine Mill and Chi-Chung Hui

Abstract:
Constantly turning over throughout adult life, the mammalian epidermis is renewed by the controlled expansion of progeny from resident multipotent stem cells. This fine balance of proliferation and differentiation of epidermal progenitors with sustained cell loss is required to maintain tissue integrity and is disturbed in many human conditions, including alopecia and skin cancer. The continuous turnover of adult skin and its appendages employs many of the same molecular and morphological programs used during embryonic development. One key player is Sonic Hedgehog (Shh) signaling, which is required for growth of embryonic and adult hair follicles,1-4 while its hyperactivation is intrinsically linked to hair follicle derived tumors in humans and mice.5-9 In both developmental and disease conditions, Shh-dependent responses are determined by the balance of activator and repressor functions of the Gli transcriptional mediators. Developments in the understanding of how this balance of Gli activities is set within target cells and what transcriptional program they execute in the skin will be the focus of this review.


Chapter:
Sonic Hedgehog Signaling in Craniofacial Development
Dwight Cordero, Minal Tapadia and Jill A. Helms

Abstract:
Facial malformations comprise a significant proportion of the anomalies observed in children born with birth defects. Although congenital facial disfigurements are relatively common and have been exhaustively categorized, science is just now beginning to unravel the genetic and environmental etiologies as well as the molecular mechanisms underlying the clinical manifestations. The Sonic Hedgehog (SHH) pathway is one important signaling pathway involved in craniofacial development. The aim of this chapter is to provide a concise review of craniofacial development within the context of recent advances in our knowledge regarding SHH signaling in facial morphogenesis. We will discuss what is known about the functions of SHH in normal and abnormal craniofacial development in humans and how nonhuman model systems are being used to build a foundation in which to understand the mechanisms underlying craniofacial malformations in humans.


Chapter:
GLI Genes and Their Targets in Epidermal Development and Disease
Fritz Aberger* and Anna-Maria Frischauf

Abstract:
During the last decade an enormous wealth of data has been generated by many different laboratories showing that the Hedgehog (HH)/GLI signaling pathway plays key roles not only in the control of vertebrate embryonic development but also in adult organisms by regulating multiple biological processes such as cell differentiation, proliferation or programmed cell death. Interest in this signaling pathway further increased by the discovery that inappropriate activation of the pathway can be associated with the development of different cancer types, ranging from relatively harmless semi-malignant tumors of the skin such as Basal Cell Carcinoma (BCC) to highly aggressive and lethal malignancies of the brain, lung or gastrointestinal tract.1-3


Chapter:
From Oligodactyly to Polydactyly: Role of Shh and Gli3 in Limb Morphogenesis
Chin Chiang

Abstract:
Secreted molecules encoded by the Hedgehog (Hh) gene family have emerged as key signals in regulating the growth and patterning of invertebrate and vertebrate embryos. One of the most prominent features among Hh members is thought to reside in their ability to impose distinct cell fates in a concentration-dependent manner. This ability is highlighted by the critical and indispensable role of Sonic hedgehog (Shh) signaling in specifying the anterior-posterior polarity of the embryonic limb. Alteration of Shh expression and signaling activity can lead to profound developmental abnormalities in digit numbers and identity in mice and humans. In this chapter, we discuss the Shh regulatory mechanism that establishes the anterior-posterior polarity of the limb and how misregulation of this mechanism can lead to severe limb malformations in humans.


Chapter:
Shh Expression in Pulmonary Injury and Disease
Paul M. Fitch, Sonia J. Wakelin, Jacqueline A. Lowrey, William A.H. Wallace and Sarah E.M. Howie

Abstract:
The Hedgehog signalling pathway is crucial for normal vertebrate growth and development. Recent studies would suggest that signalling capability is retained in the post-embryonic organism. Shh signalling has been identified in the adult immune system, participating in CD4+ T lymphocyte activation. Studies on fibrotic pulmonary disorders have demonstrated Shh in both human and mouse lung restricted to areas of active disease. Acute lung injury has also shown upregulated expression and together this data is highly suggestive for a functional role for Shh signalling in adult lung injury and disease. We propose that hedgehog signalling may contribute to epithelial injury and repair and act as an intermediary in cross-talk between damaged epithelium and the immune/inflammatory system.


Chapter
The Patched Receptor: Switching On/Off the Hedgehog Signaling Pathway
Luis Quijada, Ainhoa Callejo, Carlos Torroja and Isabel Guerrero

Abstract:
The activities of the Hedgehog (Hh) family of proteins are central to the growth and patterning of developing tissues and organs in many different organisms. Hh proteins are secreted ligands synthesized in discrete regions. The receptor of Hh is Patched (Ptc) and it is expressed in the cells close to the source of Hh. Ptc binds the ligand and transduces a signal which is modulated depending on the context and the concentration of Hh received. Hh and several molecular components of the pathway were first identified and characterized in Drosophila, providing relevant milestones to our understanding on how the Hh signal is transduced. However, important gaps in the pathway still need to be elucidated. Some of these gaps converge on the Ptc receptor and its intriguing mechanisms of Hh reception and signal transduction. Mutations of Ptc that prevail both in animal and human populations are giving some clues on crucial aspects of its function. Patients bearing mutated forms of Ptc suffer a variety of serious diseases. Molecular and cellular studies in Drosophila have given us a clue of the function of Ptc receptor such as the normal topology and/or sorting of the receptor. Thus, a widened knowledge of the function of Ptc might help to design specific therapies for these disorders. This chapter focuses on recent advances that shed some light on how Ptc may operate in the cell.


Chapter
Spatial and Temporal Regulation of Hair Follicle Progenitors by Hedgehog Signalling
Anthony E. Oro

Abstract:
Epithelial organs such as the vertebrate hair undergo programmed self-renewal in part by controlling the growth of progenitor cells. The hedgehog signaling pathway regulates progenitor growth in a variety of tissues. This chapter discusses evidence for how the skin regulates the production of Shh ligand, the reception of the Shh signal, and maintenance of the signal to promote hair morphogenesis and prevent tumor formation.


Chapter
Important Role of Shh Controlling Gli3 Functions During the Dorsal-Ventral Patterning of the Telencephalon
Jun Motoyama and Kazushi Aoto

Abstract:
The dorsal-ventral patterning of the telencephalon is a crucial for the normal brain function, because it determines the proportion of two different types of basic neurons, glutamatergic excitatory neurons and GABAergic inhibitory neurons. The secreted protein sonic hedgehog (Shh) is required for the ventral cell specification, whereas zinc finger transcription factor Gli3 seems to be important for the dorsal cell type specification. Recent studies suggest that how both Gli3 and Shh control the normal proportion of dorsal and ventral cell types to generate appropriate tissue size and shape during brain development. These observations may offer a new aspect to our understanding of activity gradient of Shh signal during brain development.


Chapter
Modulating the Hedgehog Pathway in Diseases
Frederic J. de Sauvage and Lee L. Rubin

Abstract:
The hedgehog (Hh) pathway is a signaling system that regulates a wide range of develop mental processes.10 Hh proteins act as morphogens to induce cell differentiation in a dose dependent manner, control cell proliferation, or alter cell shape. Aberrant regulation of the Hh signal caused by mutation in components of the pathway has been shown to lead to various developmental disorders18 or more recently to cancer.20,23 Most components of the Hh pathway were first identified in flies and later shown to be conserved in higher organisms. Although still incomplete, a picture of how the hedgehog signal is transmitted at the cellular level has started to emerge, allowing for potential therapeutic approaches to the treatment of diseases involving this pathway.


Chapter
Regulation of Early Events in Cell Cycle Progression by Hedgehog Signaling in CNS Devlopment and Tumorigenesis
Anna Marie Kenney and David H. Rowitch

Abstract:
Hedgehog signaling is essential for proliferation of neural precursor populations in the developing central nervous system (CNS) and is etiologic in cerebellar brain tumors. Here we will contrast general strategies of cell cycle regulation by growth factors in the developing CNS with the emerging concept of a noncanonical Hedgehog �proliferative pathway� as suggested by published studies. Mechanisms utilized by Sonic hedgehog signaling to promote cell cycle progression in CNS progenitors during development and in adult stem cell populations also contribute to CNS tumorigenesis.


Chapter
Mode of PTCH1/Ptch1-associated Tumor Formation: Insights from Mutant Ptch1 Mice
H. Hahn

Abstract:
Patched1 (PTCH1/Ptch1) is a member of the SHH/Shh signaling pathway, where it serves as a receptor for SHH/Shh. Inactivating mutations in the PTCH1/Ptch1 gene result in a pathological activation of the pathway, which may lead to several forms of familial and sporadic cancers. Although PTCH1/Ptch1 is generally supposed to be a tumor suppressor gene, mutational inactivation of one allele seems to be sufficient for tumor formation. In this chapter the current knowledge about the mode of tumor formation caused by PTCH1/Ptch1 mutations is presented. Most of the insights in these processes are derived from Ptch1 mutant mice. The impact of the genetic background on tumor susceptibility, the involvement of additional molecular pathways and epigenetic mechanisms leading to tumor formation, are discussed.


Chapter
Hedgehog Signaling in Endodermally Derived Tumors
Marina Pasca di Magliano and Matthias Hebrok

Abstract:
A relatively small number of intercellular signaling pathways, including the Hedgehog (Hh), transforming growth factor ? (TGF-beta), fibroblast growth factor (FGF), Wnt, and Notch pathways, interact to regulate embryonic development and organogenesis. In contrast to the other pathways, the mammalian Hedgehog signaling pathway is relatively compact, comprised of only three known ligands, Sonic (Shh), Indian (Ihh), and Desert Hedgehog (Dhh), and two receptors, patched 1 and 2 (Ptch1/2; (Fig. 1).23 In the absence of the ligands, Patched (Ptch) inhibits the activity of a second transmembrane protein, Smoothened (Smo). As a consequence, transcription factors of the Gli family remain inactive in the cytoplasm through interaction with a protein complex that includes Suppressor of fused su(fu).44 Upon ligand stimulation, Ptch mediated inhibition of Smo is alleviated and a cascade of events that is not fully understood results in the activation and translocation of Gli transcription factors into the nucleus where they activate the transcription of target genes. Some of these are components of the Hedgehog pathway itself, including Gli, Ptch and the Hedgehog interacting protein (Hhip). Both Ptch and Hhip are membrane proteins that attenuate the pathway by binding to and blocking diffusion of Hedgehog ligands.8,10,15,16 Therefore, the Hedgehog signaling pathway regulates itself through a negative feedback mechanism that results in increased expression of Ptch and Hhip in Hedgehog responsive cells.


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