Talk:Developmental Signals - Sonic hedgehog

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Some Recent Findings

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.

PMID: 20700498

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917215

Arsenic antagonizes the Hedgehog pathway by preventing ciliary accumulation and reducing stability of the Gli2 transcriptional effector

http://www.pnas.org/content/107/30/13432.full http://www.ncbi.nlm.nih.gov/pubmed/20624968

• 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

Introduction

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.

(More? UNSW Embryology - Molecular Development- Sonic Hedgehog | OMIM 600725)

SHH Patterning

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

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

SHH Receptors

Patched Receptor

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)

BOC/CDON Receptors

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

Megalin

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.

• Megalin OMIM 600073
• Cubulin OMIM 602997

Hedgehog-Interacting Protein

(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.