Talk:Developmental Signals - Sonic hedgehog
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Structures of human Patched and its complex with native palmitoylated sonic hedgehog
Nature. 2018 Jul 11. doi: 10.1038/s41586-018-0308-7. [Epub ahead of print]
Qi X1, Schmiege P1, Coutavas E2, Wang J3, Li X4,5.
Abstract Hedgehog (HH) signalling governs embryogenesis and adult tissue homeostasis in mammals and other multicellular organisms1-3. Whereas deficient HH signalling leads to birth defects, unrestrained HH signalling is implicated in human cancers2,4-6. N-terminally palmitoylated HH releases the repression of Patched to the oncoprotein smoothened (SMO); however, the mechanism by which HH recognizes Patched is unclear. Here we report cryo-electron microscopy structures of human patched 1 (PTCH1) alone and in complex with the N-terminal domain of 'native' sonic hedgehog (native SHH-N has both a C-terminal cholesterol and an N-terminal fatty-acid modification), at resolutions of 3.5 Å and 3.8 Å, respectively. The structure of PTCH1 has internal two-fold pseudosymmetry in the transmembrane core, which features a sterol-sensing domain and two homologous extracellular domains, resembling the architecture of Niemann-Pick C1 (NPC1) protein7. The palmitoylated N terminus of SHH-N inserts into a cavity between the extracellular domains of PTCH1 and dominates the PTCH1-SHH-N interface, which is distinct from that reported for SHH-N co-receptors8. Our biochemical assays show that SHH-N may use another interface, one that is required for its co-receptor binding, to recruit PTCH1 in the absence of a covalently attached palmitate. Our work provides atomic insights into the recognition of the N-terminal domain of HH (HH-N) by PTCH1, offers a structural basis for cooperative binding of HH-N to various receptors and serves as a molecular framework for HH signalling and its malfunction in disease. PMID: 29995851 DOI: 10.1038/s41586-018-0308-7
Sonic hedgehog from pharyngeal arch 1 epithelium is necessary for early mandibular arch cell survival and later cartilage condensation differentiation
Dev Dyn. 2015 Apr;244(4):564-76. doi: 10.1002/dvdy.24256. Epub 2015 Mar 13.
Billmyre KK1, Klingensmith J.
BACKGROUND: Morphogenesis of vertebrate craniofacial skeletal elements is dependent on a key cell population, the cranial neural crest cells (NCC). Cranial NCC are formed dorsally in the cranial neural tube and migrate ventrally to form craniofacial skeletal elements as well as other tissues. Multiple extracellular signaling pathways regulate the migration, survival, proliferation, and differentiation of NCC.
RESULTS: In this study, we demonstrate that Shh expression in the oral ectoderm and pharyngeal endoderm is essential for mandibular development. We show that a loss of Shh in these domains results in increased mesenchymal cell death in pharyngeal arch 1 (PA1) after NCC migration. This increased cell death can be rescued in utero by pharmacological inhibition of p53. Furthermore, we show that epithelial SHH is necessary for the early differentiation of mandibular cartilage condensations and, therefore, the subsequent development of Meckel's cartilage, around which the dentary bone forms. Nonetheless, a rescue of the cell death phenotype does not rescue the defect in cartilage condensation formation.
CONCLUSIONS: Our results show that SHH produced by the PA1 epithelium is necessary for the survival of post-migratory NCC, and suggests a key role in the subsequent differentiation of chondrocytes to form Meckel's cartilage.
© 2015 Wiley Periodicals, Inc.
KEYWORDS: chondrogenesis; micrognathia; neural crest cells PMID: 25626636 DOI: 10.1002/dvdy.24256
Multisite interaction with Sufu regulates Ci/Gli activity through distinct mechanisms in Hh signal transduction
Proc Natl Acad Sci U S A. 2015 May 19;112(20):6383-8. doi: 10.1073/pnas.1421628112. Epub 2015 May 4.
Han Y1, Shi Q1, Jiang J2.
Abstract The tumor suppressor protein Suppressor of fused (Sufu) plays a conserved role in the Hedgehog (Hh) signaling pathway by inhibiting Cubitus interruptus (Ci)/Glioma-associated oncogene homolog (Gli) transcription factors, but the molecular mechanism by which Sufu inhibits Ci/Gli activity remains poorly understood. Here we show that Sufu can bind Ci/Gli through a C-terminal Sufu-interacting site (SIC) in addition to a previously identified N-terminal site (SIN), and that both SIC and SIN are required for optimal inhibition of Ci/Gli by Sufu. We show that Sufu can sequester Ci/Gli in the cytoplasm through binding to SIN while inhibiting Ci/Gli activity in the nucleus depending on SIC. We also find that binding of Sufu to SIC and the middle region of Ci can impede recruitment of the transcriptional coactivator CBP by masking its binding site in the C-terminal region of Ci. Indeed, moving the CBP-binding site to an "exposed" location can render Ci resistant to Sufu-mediated inhibition in the nucleus. Hence, our study identifies a previously unidentified and conserved Sufu-binding motif in the C-terminal region of Ci/Gli and provides mechanistic insight into how Sufu inhibits Ci/Gli activity in the nucleus. KEYWORDS: CBP; Ci; Gli; Hedgehog; Sufu
Secreted HHIP1 interacts with heparan sulfate and regulates Hedgehog ligand localization and function
J Cell Biol. 2015 Jun 8;209(5):739-57. doi: 10.1083/jcb.201411024.
Holtz AM1, Griffiths SC2, Davis SJ3, Bishop B2, Siebold C2, Allen BL4.
Vertebrate Hedgehog (HH) signaling is controlled by several ligand-binding antagonists including Patched-1 (PTCH1), PTCH2, and HH-interacting protein 1 (HHIP1), whose collective action is essential for proper HH pathway activity. However, the molecular mechanisms used by these inhibitors remain poorly understood. In this paper, we investigated the mechanisms underlying HHIP1 antagonism of HH signaling. Strikingly, we found evidence that HHIP1 non-cell-autonomously inhibits HH-dependent neural progenitor patterning and proliferation. Furthermore, this non-cell-autonomous antagonism of HH signaling results from the secretion of HHIP1 that is modulated by cell type-specific interactions with heparan sulfate (HS). These interactions are mediated by an HS-binding motif in the cysteine-rich domain of HHIP1 that is required for its localization to the neuroepithelial basement membrane (BM) to effectively antagonize HH pathway function. Our data also suggest that endogenous, secreted HHIP1 localization to HS-containing BMs regulates HH ligand distribution. Overall, the secreted activity of HHIP1 represents a novel mechanism to regulate HH ligand localization and function during embryogenesis. © 2015 Holtz et al.
Disruption of Scube2 impairs endochondral bone formation
J Bone Miner Res. 2015 Jan 12. doi: 10.1002/jbmr.2451. [Epub ahead of print]
Lin YC1, Roffler SR, Yan YT, Yang RB.
SCUBE2 (signal peptide-CUB-EGF domain-containing protein 2) belongs to a secreted and membrane-tethered multi-domain SCUBE protein family composed of 3 members found in vertebrates and mammals. Recent reports suggested that zebrafish scube2 could facilitate sonic hedgehog (Shh) signaling for proper development of slow muscle. However, whether SCUBE2 can regulate the signaling activity of two other hedgehog ligands (Ihh and Dhh), and the developmental relevance of the SCUBE2-induced hedgehog signaling in mammals remain poorly understood. In this study, we first showed that as compared with SCUBE1 or 3, SCUBE2 is the most potent modulator of IHH signaling in vitro. In addition, gain and loss-of-function studies demonstrated that SCUBE2 exerted an osteogenic function by enhancing Ihh-stimulated osteoblast differentiation in the mouse mesenchymal progenitor cells. Consistent with these in vitro studies and the prominent roles of Ihh in coordinating skeletogenesis, genetic ablation of Scube2 (-/-) caused defective endochondral bone formation and impaired Ihh-mediated chondrocyte differentiation and proliferation as well as osteoblast differentiation of -/- bone-marrow mesenchymal stromal-cell cultures. Our data demonstrate that Scube2 plays a key regulatory role in Ihh-dependent endochondral bone formation. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved. KEYWORDS: Bone µCT; Genetic animal models; Hedgehogs; Molecular pathways - development; osteoblast
Mapping the Shh long-range regulatory domain
Development. 2014 Oct;141(20):3934-43. doi: 10.1242/dev.108480. Epub 2014 Sep 24.
Anderson E1, Devenney PS1, Hill RE2, Lettice LA1.
Coordinated gene expression controlled by long-distance enhancers is orchestrated by DNA regulatory sequences involving transcription factors and layers of control mechanisms. The Shh gene and well-established regulators are an example of genomic composition in which enhancers reside in a large desert extending into neighbouring genes to control the spatiotemporal pattern of expression. Exploiting the local hopping activity of the Sleeping Beauty transposon, the lacZ reporter gene was dispersed throughout the Shh region to systematically map the genomic features responsible for expression activity. We found that enhancer activities are retained inside a genomic region that corresponds to the topological associated domain (TAD) defined by Hi-C. This domain of approximately 900 kb is in an open conformation over its length and is generally susceptible to all Shh enhancers. Similar to the distal enhancers, an enhancer residing within the Shh second intron activates the reporter gene located at distances of hundreds of kilobases away, suggesting that both proximal and distal enhancers have the capacity to survey the Shh topological domain to recognise potential promoters. The widely expressed Rnf32 gene lying within the Shh domain evades enhancer activities by a process that may be common among other housekeeping genes that reside in large regulatory domains. Finally, the boundaries of the Shh TAD do not represent the absolute expression limits of enhancer activity, as expression activity is lost stepwise at a number of genomic positions at the verges of these domains. © 2014. Published by The Company of Biologists Ltd. KEYWORDS: Enhancers; Long-range regulation; Mouse; Sleeping beauty transposon; Sonic hedgehog (Shh); Topological domains
Sonic hedgehog signaling regulates mode of cell division of early cerebral cortex progenitors and increases astrogliogenesis
Front Cell Neurosci. 2014 Mar 11;8:77. doi: 10.3389/fncel.2014.00077. eCollection 2014.
Araújo GL1, Araújo JA1, Schroeder T2, Tort AB1, Costa MR1. Author information
Abstract The morphogen Sonic Hedgehog (SHH) plays a critical role in the development of different tissues. In the central nervous system, SHH is well known to contribute to the patterning of the spinal cord and separation of the brain hemispheres. In addition, it has recently been shown that SHH signaling also contributes to the patterning of the telencephalon and establishment of adult neurogenic niches. In this work, we investigated whether SHH signaling influences the behavior of neural progenitors isolated from the dorsal telencephalon, which generate excitatory neurons and macroglial cells in vitro. We observed that SHH increases proliferation of cortical progenitors and generation of astrocytes, whereas blocking SHH signaling with cyclopamine has opposite effects. In both cases, generation of neurons did not seem to be affected. However, cell survival was broadly affected by blockade of SHH signaling. SHH effects were related to three different cell phenomena: mode of cell division, cell cycle length and cell growth. Together, our data in vitro demonstrate that SHH signaling controls cell behaviors that are important for proliferation of cerebral cortex progenitors, as well as differentiation and survival of neurons and astroglial cells. KEYWORDS: astrocytes, cell survival, cerebral cortex development, gliogenesis, mode of cell division, neurogenesis, progenitor cells, sonic hedgehog (SHH)
GATA6 Is a Crucial Regulator of Shh in the Limb Bud
PLoS Genet. 2014 Jan;10(1):e1004072. doi: 10.1371/journal.pgen.1004072. Epub 2014 Jan 9.
Kozhemyakina E, Ionescu A, Lassar AB. Author information
Abstract In the limb bud, patterning along the anterior-posterior (A-P) axis is controlled by Sonic Hedgehog (Shh), a signaling molecule secreted by the "Zone of Polarizing Activity", an organizer tissue located in the posterior margin of the limb bud. We have found that the transcription factors GATA4 and GATA6, which are key regulators of cell identity, are expressed in an anterior to posterior gradient in the early limb bud, raising the possibility that GATA transcription factors may play an additional role in patterning this tissue. While both GATA4 and GATA6 are expressed in an A-P gradient in the forelimb buds, the hindlimb buds principally express GATA6 in an A-P gradient. Thus, to specifically examine the role of GATA6 in limb patterning we generated Prx1-Cre; GATA6(fl/fl) mice, which conditionally delete GATA6 from their developing limb buds. We found that these animals display ectopic expression of both Shh and its transcriptional targets specifically in the anterior mesenchyme of the hindlimb buds. Loss of GATA6 in the developing limbs results in the formation of preaxial polydactyly in the hindlimbs. Conversely, forced expression of GATA6 throughout the limb bud represses expression of Shh and results in hypomorphic limbs. We have found that GATA6 can bind to chromatin (isolated from limb buds) encoding either Shh or Gli1 regulatory elements that drive expression of these genes in this tissue, and demonstrated that GATA6 works synergistically with FOG co-factors to repress expression of luciferase reporters driven by these sequences. Most significantly, we have found that conditional loss of Shh in limb buds lacking GATA6 prevents development of hindlimb polydactyly in these compound mutant embryos, indicating that GATA6 expression in the anterior region of the limb bud blocks hindlimb polydactyly by repressing ectopic expression of Shh.
How is digit identity determined during limb development?
Dev Growth Differ. 2013 Jan;55(1):130-8. doi: 10.1111/dgd.12022. Epub 2012 Dec 12.
Suzuki T. Source Division of Biological Science, Graduate School of Science, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, Japan. firstname.lastname@example.org
Digit identity has been studied using the chick embryo as a model system for more than 40 years. Using this model system, several milestone findings have been reported, such as the apical ectodermal ridge (AER), the zone of polarizing activity (ZPA), the Shh gene, and the theory of morphogen and positional information. These experimental results and models provided context for understanding pattern formation in developmental biology. The focus of this review is on the determination of digit identity during limb development. First, the history of studies on digit identity determination is described, followed by descriptions of the molecular mechanisms and current models for determination of digit identity. Finally, future questions and remarkable points will be discussed. © 2012 The Authors Development, Growth & Differentiation © 2012 Japanese Society of Developmental Biologists.
Mathematical modelling of digit specification by a sonic hedgehog gradient
Dev Dyn. 2013 Oct 2. doi: 10.1002/dvdy.24068. [Epub ahead of print]
Woolley TE, Baker RE, Tickle C, Maini PK, Towers M. Source Centre for Mathematical Biology Mathematical Institute, University of Oxford, 24-29 St Giles', Oxford, OX1 3LB, UK. Abstract Background: The three chick wing digits represent a classical example of a pattern specified by a morphogen gradient. Here we have investigated whether a mathematical model of a Shh gradient can describe the specification of the identities of the three chick wing digits and if it can be applied to limbs with more digits. Results: We have produced a mathematical model for specification of chick wing digit identities by a Shh gradient that can be extended to the four digits of the chick leg with Shh-producing cells forming a digit. This model cannot be extended to specify the five digits of the mouse limb. Conclusions: Our data suggest that the parameters of a classical-type morphogen gradient are sufficient to specify the identities of three different digits. However, to specify more digits identities this core mechanism has to be coupled to alternative processes: one being that in the chick leg and mouse limb, Shh-producing cells give rise to digits; another that in the mouse limb, the cellular response to the Shh gradient adapts over time so that digit specification does not depend simply on Shh concentration. Developmental Dynamics, 2013. © 2013 Wiley Periodicals, Inc. ©2013. Wiley Periodicals, Inc. KEYWORDS: Chick wing, Diffusion, Digits, Gradient, Growth, Limb, Mathematical modelling, Morphogen, Shh
Ontogenetic expression of sonic hedgehog in the chicken subpallium
Front Neuroanat. 2010 Jul 21;4. pii: 28.
Bardet SM, Ferran JL, Sanchez-Arrones L, Puelles L.
Unité de Génétique Moléculaire Animale-INRA UMR 1061, University of Limoges Limoges, France. Abstract Sonic hedgehog (SHH) is a secreted signaling factor that is implicated in the molecular patterning of the central nervous system (CNS), somites, and limbs in vertebrates. SHH has a crucial role in the generation of ventral cell types along the entire rostrocaudal axis of the neural tube. It is secreted early in development by the axial mesoderm (prechordal plate and notochord) and the overlying ventral neural tube. Recent studies clarified the impact of SHH signaling mechanisms on dorsoventral patterning of the spinal cord, but the corresponding phenomena in the rostral forebrain are slightly different and more complex. This notably involves separate Shh expression in the preoptic part of the forebrain alar plate, as well as in the hypothalamic floor and basal plates. The present work includes a detailed spatiotemporal description of the singular alar Shh expression pattern in the rostral preoptic forebrain of chick embryos, comparing it with FoxG1, Dlx5, Nkx2.1, and Nkx2.2 mRNA expression at diverse stages of development. As a result of this mapping, we report a subdivision of the preoptic region in dorsal and ventral zones; only the dorsal part shows Shh expression. The positive area impinges as well upon a median septocommissural preoptic domain. Our study strongly suggests tangential migration of Shh-positive cells from the preoptic region into other subpallial domains, particularly into the pallidal mantle and the intermediate septum.
Arsenic antagonizes the Hedgehog pathway by preventing ciliary accumulation and reducing stability of the Gli2 transcriptional effector
- Dynamic Assignment and Maintenance of Positional Identity in the Ventral Neural Tube by the Morphogen Sonic Hedgehog http://www.ncbi.nlm.nih.gov/pubmed/20532235 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2879390/
- All mammalian hedgehog proteins interact with CDO and BOC in a conserved manner. http://www.ncbi.nlm.nih.gov/pubmed/20519495
- Mouse hitchhiker mutants have spina bifida, dorso-ventral patterning defects and polydactyly: identification of Tulp3 as a novel negative regulator of the Sonic hedgehog pathway. http://www.ncbi.nlm.nih.gov/pubmed/19223390
- Dynamic interpretation of hedgehog signaling in the Drosophila wing disc. 
- Patched 1 is a crucial determinant of asymmetry and digit number in the vertebrate limb.
- Uncoupling Sonic hedgehog control of pattern and expansion of the developing limb bud. "One of the first changes we noted was that the dorsoventral polarity of the forebrain was disturbed, which manifested as a loss of Shh in the ventral telencephalon, a reduction in expression of the ventral markers Nkx2.1 and Dlx2, and a concomitant expansion of the dorsal marker Pax6. In addition to changes in the forebrain neuroectoderm, we observed altered gene expression patterns in the facial ectoderm. For example, Shh was not induced in the frontonasal ectoderm, and Ptc and Gli1 were reduced in both the ectoderm and adjacent mesenchyme."
- THM1 negatively modulates mouse sonic hedgehog signal transduction and affects retrograde intraflagellar transport in cilia.
- Triphalangeal thumb-polysyndactyly syndrome and syndactyly type IV are caused by genomic duplications involving the long-range, limb-specific SHH enhancer.
- Notochord-derived Shh concentrates in close association with the apically positioned basal body in neural target cells and forms a dynamic gradient during neural patterning. 
A gradient of Gli activity mediates graded Sonic Hedgehog signaling in the neural tube. 15741323
Some Recent Findings
- Patched 1 is a crucial determinant of asymmetry and digit number in the vertebrate limb. Butterfield NC, Metzis V, McGlinn E, Bruce SJ, Wainwright BJ, Wicking C. Development. 2009 Oct;136(20):3515-24. PMID: 19783740
- Sonic hedgehog-dependent synthesis of laminin alpha1 controls basement membrane assembly in the myotome. Anderson C, Thorsteinsdóttir S, Borycki AG. Development. 2009 Oct;136(20):3495-504. PMID: 19783738
- Molecular and tissue interactions governing induction of cranial ectodermal placodes. McCabe KL, Bronner-Fraser M. Dev Biol. 2009 Aug 15;332(2):189-95. Epub 2009 Jun 2. Review. PMID: 19500565
- <pubmed>19787036</pubmed> | PLOS
The Hedgehog (Hh) family of regulation factors is a wonderful story of serendipity and the establishment of linking all species development to similar signals. Conceptually this mechanism of signaling shows how the same signal can mean different things in different tissues at different times.
Hedgehog (Hh) was initially named after a drosophila (fly) mutant which during embryonic development had prominant changes in regions which should be bare surface cuticle, the fly therefore looked like a "hedgehog". The human homolog gene is located on chromosome 7 (7q36).
Sonic Hedgehog (SHH) was isolated by homology to the Hh gene. SHH is a true signaling switch used in differentiating subpopulations of cells throughout the embryo. Depending on where the signal is being secreted, how far away the responsive cell population is and how SHH is proteolytically cleaved, will determine SHH function. SHH binds to the membrane receptors Patched (ptc) and BOC/CDON.
Below are listed some examples of hedgehog signaling in differet regions and tissues of the developing embryo. More information can be found on pages and lectures related to each topic.
- Neural Ectodem Ventral neural tube (basal plate, motor columns)
- Developing Brain
- Ectoderm Hair Follicle Development, Tooth Development
- Lung Development
- Pancreas Development
- Limb Bud Image: chick limb development
- External Genitalia
- Multiphasic and tissue-specific roles of sonic hedgehog in cloacal septation and external genitalia development. Seifert AW, Bouldin CM, Choi KS, Harfe BD, Cohn MJ. Development. 2009 Dec;136(23):3949-57. PMID: 19906862
- "Within the genital tubercle, the endodermally derived urethral epithelium functions as an organizer and expresses sonic hedgehog (Shh).....Disruption of Shh function during the anogenital phase causes coordinated anorectal and genitourinary malformations, whereas inactivation during the external genital phase causes hypospadias. Shh directs cloacal septation by promoting cell proliferation in adjacent urorectal septum mesenchyme. Additionally, conditional inactivation of smoothened in the genital ectoderm and cloacal/urethral endoderm shows that the ectoderm is a direct target of Shh and is required for urethral tube closure, highlighting a novel role for genital ectoderm in urethragenesis."
- Sonic hedgehog signaling from the urethral epithelium controls external genital development. Perriton CL, Powles N, Chiang C, Maconochie MK, Cohn MJ. Dev Biol. 2002 Jul 1;247(1):26-46. PMID: 12074550
- Unique functions of Sonic hedgehog signaling during external genitalia development. Haraguchi R, Mo R, Hui C, Motoyama J, Makino S, Shiroishi T, Gaffield W, Yamada G. Development. 2001 Nov;128(21):4241-50. PMID: 11684660
In the fly, D. melanogaster, patched (ptc) is a protein ligand receptor involved in the smo receptor signalling pathway which is a component of the integral plasma membrane protein. There are homologues in Homo sapiens , Mus , Caenorhabditis elegans , Drosophila sp. , Mus musculus and Saccharomyces cerevisiae.
D. melanogaster expression in the embryo (Malpighian tubule , analia , embryonic/larval hindgut , head and 2 other listed tissues). Protein interacts genetically with fu , rho , hh , ci , gsb , B , kn , N , l(1)sc , smo , Su(fu) and vn . There are 62 recorded mutant alleles , of which at least 16 are available from the public stock centers. Amorphic mutations have been isolated which affect the anterior wing , the costal cell , the wing vein and 8 other listed tissues and are embryonic lethal, visible and tissue polarity. ptc is discussed in 325 published references , dated between 1948 and 1999. These include at least 58 studies of mutant phenotypes , one study of wild-type function and 4 molecular studies . Among findings on ptc mutants, ptc mutant analysis and stage-specific laser inactivation of ptc protein indicates that ptc activity is functionally redeployed after the segmentation phenocritical period to discriminate between neural and epithelial cell fates. (Some text modified from Flybase entry for Hedgehog Gene and refers to the fruitfly hh gene)
Two recently identified related receptors for SHH, Boc and Cdon are cell surface receptors of the immunoglobulin (Ig)/fibronectin type III that interact with each other and are coexpressed in development.
- Brother of Cdon (BOC) OMIM 608708
- Cell adhesion molecule-regulated/downregulated by oncogenes (CDON) OMIM 608707
In development, it has been shown that sonic hedgehog can also bind megalin (lipoprotein receptor-related protein-2, LRP2, gp330) a transmembrane protein which acts as an endocytic receptor on the apical surface of polarised epithelial cells. It requires interaction with another protein, cubulin, for the endocytosis of ligands.
(Hhip) A surface receptor antagonist that is equipotent against all three mammalian Hh homologs. The structure of human HHIP is comprised of two EGF domains and a six-bladed beta-propeller domain.