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Elaine Y C Hsia, Ya Zhang, Hai Son Tran, Agnes Lim, Ya-Hui Chou, Ganhui Lan, Philip A Beachy, Xiaoyan Zheng
The Drosophila Hedgehog receptor functions to regulate the essential downstream pathway component, Smoothened, and to limit the range of signaling by sequestering Hedgehog protein signal within imaginal disc epithelium. Hedgehog receptor function requires both Patched and Ihog activity, the latter interchangeably encoded by interference hedgehog (ihog) or brother of ihog (boi). Here we show that Patched and Ihog activity are mutually required for receptor endocytosis and degradation, triggered by Hedgehog protein binding, and causing reduced levels of Ihog/Boi proteins in a stripe of cells at the anterior/posterior compartment boundary of the wing imaginal disc...
November 2, 2017: Nature Communications
Laura González-Méndez, Irene Seijo-Barandiarán, Isabel Guerrero
Morphogens regulate tissue patterning through their distribution in concentration gradients. Emerging research establishes a role for specialized signalling filopodia, or cytonemes, in morphogen dispersion and signalling. Previously we demonstrated that Hedgehog (Hh) morphogen is transported via vesicles along cytonemes emanating from signal-producing cells to form a gradient in Drosophila epithelia. However, the mechanisms for signal reception and transfer are still undefined. Here, we demonstrate that cytonemes protruding from Hh-receiving cells contribute to Hh gradient formation...
August 21, 2017: ELife
Kai Jiang, Yajuan Liu, Junkai Fan, Jie Zhang, Xiang-An Li, B Mark Evers, Haining Zhu, Jianhang Jia
In Hedgehog (Hh) signaling, binding of Hh to the Patched-Interference Hh (Ptc-Ihog) receptor complex relieves Ptc inhibition on Smoothened (Smo). A longstanding question is how Ptc inhibits Smo and how such inhibition is relieved by Hh stimulation. In this study, we found that Hh elevates production of phosphatidylinositol 4-phosphate (PI(4)P). Increased levels of PI(4)P promote, whereas decreased levels of PI(4)P inhibit, Hh signaling activity. We further found that PI(4)P directly binds Smo through an arginine motif, which then triggers Smo phosphorylation and activation...
February 2016: PLoS Biology
Kai Jiang, Jianhang Jia
Smoothened (Smo) is essential for transduction of the Hedgehog (Hh) signal in both insects and vertebrates. Binding of Hh to Ptc-Ihog relieves the Patched (Ptc)-mediated inhibition of Smo, which allows Smo to activate the cubitus interruptus (Ci)/Gli family of zinc finger transcription factors and thereby induce the expression of Hh target genes, such as decapentaplegic (dpp), ptc, and engrailed (en). The activation of Smo appears to be one of the most important events in Hh signaling. Studies have shown that Hh induces cell surface/ciliary accumulation and phosphorylation of Smo by multiple kinases, including protein kinase A (PKA), casein kinase 1 (CK1), casein kinase 2 (CK2), G protein-coupled receptor kinase 2 (Gprk2), and atypical PKC (aPKC)...
2015: Methods in Molecular Biology
Ana-Citlali Gradilla, Esperanza González, Irene Seijo, German Andrés, Marcus Bischoff, Laura González-Mendez, Vanessa Sánchez, Ainhoa Callejo, Carmen Ibáñez, Milagros Guerra, João Ramalho Ortigão-Farias, James D Sutherland, Monika González, Rosa Barrio, Juan M Falcón-Pérez, Isabel Guerrero
The Hedgehog signalling pathway is crucial for development, adult stem cell maintenance, cell migration and axon guidance in a wide range of organisms. During development, the Hh morphogen directs tissue patterning according to a concentration gradient. Lipid modifications on Hh are needed to achieve graded distribution, leading to debate about how Hh is transported to target cells despite being membrane-tethered. Cytonemes in the region of Hh signalling have been shown to be essential for gradient formation, but the carrier of the morphogen is yet to be defined...
2014: Nature Communications
Thomas E Cleveland, Jacqueline M McCabe, Daniel J Leahy
Patched (Ptc) is a twelve-pass transmembrane protein that functions as a receptor for the Hedgehog (Hh) family of morphogens. In addition to Ptc, several accessory proteins including the CDO/Ihog family of co-receptors are necessary for proper Hh signaling. Structures of Hh proteins bound to members of the CDO/Ihog family are known, but the nature of the full Hh receptor complex is not well understood. We have expressed the Drosophila Patched and Mouse Patched-1 proteins in Sf9 cells and find that Sonic Hedgehog will bind to Mouse Patched-1 in isolated Sf9 cell membranes but that purified, detergent-solubilized Ptc proteins do not interact strongly with cognate Hh and CDO/Ihog homologs...
December 2014: Protein Expression and Purification
Darius Camp, Billy Haitian He, Sally Li, Irene W Althaus, Alexander M Holtz, Benjamin L Allen, Frédéric Charron, Donald J van Meyel
Hedgehog (Hh) proteins are secreted molecules essential for tissue development in vertebrates and invertebrates. Hh reception via the 12-pass transmembrane protein Patched (Ptc) elicits intracellular signaling through Smoothened (Smo). Hh binding to Ptc is also proposed to sequester the ligand, limiting its spatial range of activity. In Drosophila, Interference hedgehog (Ihog) and Brother of ihog (Boi) are two conserved and redundant transmembrane proteins that are essential for Hh pathway activation. How Ihog and Boi activate signaling in response to Hh remains unknown; each can bind both Hh and Ptc and so it has been proposed that they are essential for both Hh reception and sequestration...
October 2014: Development
Vanina G Da Ros, Irene Gutierrez-Perez, Dolors Ferres-Marco, Maria Dominguez
Fine-tuned Notch and Hedgehog signalling pathways via attenuators and dampers have long been recognized as important mechanisms to ensure the proper size and differentiation of many organs and tissues. This notion is further supported by identification of mutations in these pathways in human cancer cells. However, although it is common that the Notch and Hedgehog pathways influence growth and patterning within the same organ through the establishment of organizing regions, the cross-talk between these two pathways and how the distinct organizing activities are integrated during growth is poorly understood...
2013: PLoS Biology
Lei Gao, Longfei Wu, Xiaomeng Hou, Qinghai Zhang, Feifei Zhang, Xiaolei Ye, Yongfei Yang, Xinhua Lin
Hedgehog (Hh) proteins act as morphogens in a variety of developmental contexts to control cell fates and growth in a concentration-dependent manner. Therefore, secretion, distribution, and reception of Hh proteins must be tightly regulated and deregulation of these processes contributes to numerous human diseases. Brother of ihog (Boi) and its close relative Ihog (Interference hedgehog) are cell surface proteins that act as Hh co-receptors required for Hh signaling response and cell-surface maintenance of Hh protein...
May 1, 2013: Developmental Biology
Aphrodite Bilioni, David Sánchez-Hernández, Ainhoa Callejo, Ana-Citlali Gradilla, Carmen Ibáñez, Emanuela Mollica, M Carmen Rodríguez-Navas, Eléanor Simon, Isabel Guerrero
Hedgehog can signal both at a short and long-range, and acts as a morphogen during development in various systems. We studied the mechanisms of Hh release and spread using the Drosophila wing imaginal disc as a model system for polarized epithelium. We analyzed the cooperative role of the glypican Dally, the extracellular factor Shifted (Shf, also known as DmWif), and the Immunoglobulin-like (Ig-like) and Fibronectin III (FNNIII) domain-containing transmembrane proteins, Interference hedgehog (Ihog) and its related protein Brother of Ihog (Boi), in the stability, release and spread of Hh...
April 15, 2013: Developmental Biology
Andrei Avanesov, Seth S Blair
Hedgehog (Hh) family proteins are secreted signaling ligands whose short- and long-range activities transform cellular fates in multiple contexts in organisms ranging from metazoans to humans. In the developing Drosophila wing, extracellular Hh binds to cell-bound glypican heparan sulfate proteoglycans (HSPGs) and the secreted protein Shifted (Shf), a member of Wnt inhibitory factor 1 (WIF1) family. The glypicans and Shf are required for long-range Hh movement and signaling; it has been proposed that Shf promotes long-range Hh signaling by reinforcing binding between Hh and the glypicans, and that much or all of glypican function in Hh signaling requires Shf...
January 1, 2013: Development
Luisa Sanchez-Arrones, Marcos Cardozo, Francisco Nieto-Lopez, Paola Bovolenta
Cdon and Boc, and their Drosophila homologues Ihog and Boi, are evolutionary conserved transmembrane glycoproteins belonging to a subgroup of the Immunoglobulin superfamily of cell adhesion molecules (CAMs). Initially isolated in vertebrates as CAMs that link cadherin function with MAPK signaling in myoblast differentiation, they have thereafter been shown to act as essential receptors for the Hedgehog (Hh) family of secreted proteins. They associate with both ligand and other Hh receptor components, including Ptch and Gas1, thus forming homo- and heteromeric complexes...
May 2012: International Journal of Biochemistry & Cell Biology
Min-Sung Kim, Adam M Saunders, Brent Y Hamaoka, Philip A Beachy, Daniel J Leahy
Glypicans are heparan sulfate proteoglycans that modulate the signaling of multiple growth factors active during animal development, and loss of glypican function is associated with widespread developmental abnormalities. Glypicans consist of a conserved, approximately 45-kDa N-terminal protein core region followed by a stalk region that is tethered to the cell membrane by a glycosyl-phosphatidylinositol anchor. The stalk regions are predicted to be random coil but contain a variable number of attachment sites for heparan sulfate chains...
August 9, 2011: Proceedings of the National Academy of Sciences of the United States of America
Ainhoa Callejo, Aphrodite Bilioni, Emanuela Mollica, Nicole Gorfinkiel, Germán Andrés, Carmen Ibáñez, Carlos Torroja, Laura Doglio, Javier Sierra, Isabel Guerrero
Hedgehog (Hh) moves from the producing cells to regulate the growth and development of distant cells in a variety of tissues. Here, we have investigated the mechanism of Hh release from the producing cells to form a morphogenetic gradient in the Drosophila wing imaginal disk epithelium. We describe that Hh reaches both apical and basolateral plasma membranes, but the apical Hh is subsequently internalized in the producing cells and routed to the basolateral surface, where Hh is released to form a long-range gradient...
August 2, 2011: Proceedings of the National Academy of Sciences of the United States of America
Luisa Izzi, Martin Lévesque, Steves Morin, Dominique Laniel, Brian C Wilkes, Frédéric Mille, Robert S Krauss, Andrew P McMahon, Benjamin L Allen, Frédéric Charron
Hedgehog (Hh) proteins regulate important developmental processes, including cell proliferation and differentiation. Although Patched acts as the main Hh receptor in Drosophila, Hh signaling absolutely requires the additional Hh-binding proteins Ihog and Boi. Here we show that, unexpectedly, cerebellar granule neuron progenitors (CGNPs) lacking Boc and Cdon, the vertebrate orthologs of Ihog and Boi, still proliferate in response to Hh. This is because in their absence, Gas1, an Hh-binding protein not present in Drosophila, mediates Hh signaling...
June 14, 2011: Developmental Cell
Wei Zhang, Mingi Hong, Gyu-un Bae, Jong-Sun Kang, Robert S Krauss
Holoprosencephaly (HPE) is caused by a failure to form the midline of the forebrain and/or midface. It is one of the most common human birth defects, but clinical expression is extremely variable. HPE is associated with mutations in the sonic hedgehog (SHH) pathway. Mice lacking the Shh pathway regulator Cdo (also called Cdon) display HPE with strain-dependent penetrance and expressivity, implicating silent modifier genes as one cause of the variability. However, the identities of potential HPE modifiers of this type are unknown...
May 2011: Disease Models & Mechanisms
Darius Camp, Ko Currie, Alain Labbé, Donald J van Meyel, Frédéric Charron
BACKGROUND: The Hedgehog (Hh) signaling pathway is important for the development of a variety of tissues in both vertebrates and invertebrates. For example, in developing nervous systems Hh signaling is required for the normal differentiation of neural progenitors into mature neurons. The molecular signaling mechanism underlying the function of Hh is not fully understood. In Drosophila, Ihog (Interference hedgehog) and Boi (Brother of Ihog) are related transmembrane proteins of the immunoglobulin superfamily (IgSF) with orthologs in vertebrates...
2010: Neural Development
Philip A Beachy, Sarah G Hymowitz, Robert A Lazarus, Daniel J Leahy, Christian Siebold
Hedgehog (Hh) proteins are secreted signaling molecules that mediate essential tissue-patterning events during embryonic development and function in tissue homeostasis and regeneration throughout life. Hh signaling is regulated by multiple mechanisms, including covalent lipid modification of the Hh protein and interactions with multiple protein and glycan partners. Unraveling the nature and effects of these interactions has proven challenging, but recent structural and biophysical studies of Hh proteins and active fragments of heparin, Ihog, Cdo, Boc, Hedgehog-interacting protein (Hhip), Patched (Ptc), and the monoclonal antibody 5E1 have added a new level of molecular detail to our understanding of how Hh signal response and distribution are regulated within tissues...
September 15, 2010: Genes & Development
Jennifer M Kavran, Matthew D Ward, Oyindamola O Oladosu, Sabin Mulepati, Daniel J Leahy
Hedgehog (Hh) signaling proteins stimulate cell proliferation, differentiation, and tissue patterning at multiple points in animal development. A single Hh homolog is present in Drosophila, but three Hh homologs, Sonic Hh, Indian Hh, and Desert Hh, are present in mammals. Distribution, movement, and reception of Hh signals are tightly regulated, and abnormal Hh signaling is associated with developmental defects and cancer. In addition to the integral membrane proteins Patched and Smoothened, members of the Drosophila Ihog family of adhesion-like molecules have recently been shown to bind Hh proteins with micromolar affinity and positively regulate Hh signaling...
August 6, 2010: Journal of Biological Chemistry
Dong Yan, Yihui Wu, Yongfei Yang, Tatyana Y Belenkaya, Xiaofang Tang, Xinhua Lin
Hedgehog (Hh) acts as a morphogen in various developmental contexts to specify distinct cell fates in a concentration-dependent manner. Hh signaling is regulated by two conserved cell-surface proteins: Ig/fibronectin superfamily member Interference hedgehog (Ihog) and Dally-like (Dlp), a glypican that comprises a core protein and heparan sulfate glycosaminoglycan (GAG) chains. Here, we show in Drosophila that the Dlp core protein can interact with Hh and is essential for its function in Hh signaling. In wing discs, overexpression of Dlp increases short-range Hh signaling while reducing long-range signaling...
June 2010: Development
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