Human developmental disorders and the Sonic hedgehog pathway
Section snippets
Properties of Sonic hedgehog
The Drosophila hedgehog (hh) gene is a segment polarity gene that was initially identified in a large screen for embryonic patterning defects[1]. There are three mammalian homologs of hh: Sonic hedgehog (Shh), Desert hedgehog (Dhh) and Indian hedgehog (Ihh) (Ref. [2]). Dhh is involved in the development of male germ cells, and Ihh plays a role in cartilage development. Shh has the largest known range of biological actions and has a role in establishing left–right body asymmetry, central nervous
The Sonic hedgehog pathway
Although the Shh pathway (Fig. 2) has been most clearly delineated in Drosophila, fundamental aspects of the pathway are conserved in higher animals and are probably similar in humans[4]. In Drosophila, hh first binds to the transmembrane molecule patched (ptc). Then, ptc interacts with another transmembrane molecule, smoothened (smo), which transduces the hh signal. The serine/threonine kinase fused (fu) is a positive mediator of the hh signal, and protein kinase A, costal-2 (cos-2) and
Sonic hedgehog and holoprosencephaly
Shh is the only one of the vertebrate hh homologs that is expressed in the central nervous system. It is expressed in the notochord and floorplate and is both necessary and sufficient for establishing ventral identity in the developing neural tube[2]. Mice with homozygous-null mutations for Shh display absence of ventral cell types in the brain, associated with craniofacial anomalies, including cyclopia and proboscis-like nasal structure[21]. The murine phenotype is remarkably similar to the
Patched, nevoid basal cell carcinoma syndrome, and sporadic basal cell carcinomas
The nevoid basal cell carcinoma syndrome (NBCCS), or Gorlin syndrome, is an autosomal-dominant condition characterized by multiple basal cell carcinomas (BCCs), dyskeratotic palmar and plantar pits, and jaw cysts[32]. A large number of associated abnormalities have been recorded, including hypoplasia of the corpus callosum, cleft lip/palate, and skeletal anomalies. Linkage of NBCCS to chromosome 9q22 and the subsequent mapping of PTC to that region led to identification of PTC as the gene
Basal cell carcinomas and the Sonic hedgehog pathway
The finding that mutations in PTC were present in sporadic BCCs led investigators to determine whether other elements of the SHH pathway might also be involved in BCC pathogenesis. A mutation in SHH has been detected in a sporadic BCC (Ref. [41]). Interestingly, identical mutations were also present in carcinoma of the breast and a medulloblastoma[41]. As loss of PTC is predicted to result in increased activity of the SHH pathway, this mutation might result in a form of SHH with increased
The Sonic hedgehog pathway and limb development
In the developing limb bud, the zone of polarizing activity (ZPA), a portion of the posterior mesenchyme, provides signals that regulate anterior–posterior identity[45]. Shh is expressed in the ZPA and is responsible for the morphogenetic properties of the ZPA (Ref. [45]). Ectopic expression of Shh can lead to mirror-image duplication of digits2, 45, as is seen with grafts of the ZPA into ectopic anterior regions. In addition, decreased Shh expression in the ZPA leads to loss of the ulna and
Diseases associated with mutations in GLI3
The Gli family of transcription factors plays a role in regulating expression of target genes of Shh. Several regions of similarity are shared, including a zinc-finger domain (Fig. 4). Mutations in GLI3 can give rise to three clinically distinct syndromes. Greig cephalopolysyndactyly syndrome is characterized by preaxial or postaxial polydactyly, syndactyly and hypertelorism. Haploinsufficiency resulting from large deletions, translocations or point mutations in GLI3 was present in affected
Summary and future directions
Both animal and human studies clearly demonstrate that the Shh pathway is crucial for the normal progression of multiple developmental processes. The finding that several congenital malformation syndromes are caused by abnormalities in the SHH pathway emphasizes the importance of this morphogen. Haploinsufficiency of SHH can lead to HPE. Conversely, abnormal activation of the pathway through mutations in SHH, PTC or SMO can result in tumor formation. Mutations in GLI3 show three distinct
Glossary
Bone morphogenetic proteins (BMPs)—Secreted molecules originally identified by their ability to induce ectopic bone formation. They are now known to be involved in a variety of developmental processes in a wide range of tissues, including the brain.
Corpus callosum—Structure of the forebrain that connects the brain hemispheres.
Floorplate—The ventral midline portion of the neural tube, the embryonic nervous system.
Hamartoma—A benign tumor composed of cells normally present in the affected region
The outstanding questions
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What other elements of the Sonic hedgehog (SHH) pathway are associated with human diseases, and which diseases can be caused by mutations in more than one component of the pathway?
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What other genetic or nongenetic factors play a role in the extremely variable clinical presentation of holoprosencephaly (HPE) and nevoid basal cell carcinoma syndrome (NBCCS)?
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How do the mutations in GLI3 associated with Greig, Pallister–Hall and postaxial polydactyly syndromes differ in their effects on GLI3
Acknowledgements
We thank Dr M. Michael Cohen Jr for helpful comments on this manuscript. J.E.M. was supported in part by NIH training grant 5T32HD07107. This work was supported in part by NIH grants HD28732 and HD29862 and the Division of Intramural Research, NHGRI, NIH to M.M. The authors apologize to those researchers whose studies were not directly cited but whose work is, because of space considerations, cited in the reviews referenced.
References (49)
- et al.
The world according to hedgehog
Trends Genet.
(1997) - et al.
Recent advances in hedgehog signalling
Trends Cell Biol.
(1997) The Drosophila smoothened gene encodes a seven-pass membrane protein, a putative receptor for the hedgehog signal
Cell
(1996)Proteolysis that can be inhibited by Hedghog directs Cubitus interruptus protein to the nucleus and changes its activity as a transcriptional regulator
Cell
(1997)Hedghog elicits signal transduction by means of a large complex containing the kinesin-related protein Costal2
Cell
(1997)- et al.
Costal2, a novel kinesin-related protein in the hedgehog signalling pathway
Cell
(1997) Catching a Gli-mpse of hedgehog
Cell
(1997)Control of cell pattern in the neural tube by the zinc finger transcription factor and oncogene Gli-1
Neuron
(1997)Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome
Cell
(1996)- et al.
Molecular models or vertebrate limb development
Cell
(1997)
Mutations affecting segment number and polarity in Drosophila
Nature
Cholesterol modification of hedgehog signaling proteins in animal development
Science
The tumor suppressor gene patched encodes a candidate receptor for Sonic hedgehog
Nature
Biochemical evidence that Patched is the hedgehog receptor
Nature
Niemann–Pick C1 disease gene: Homology to mediators of cholesterol homeostasis
Science
Developmental genes and cancer: role of Patched in basal cell carcinoma of the skin
J. Natl. Cancer Inst.
Smoothened encodes a receptor-like serpentine protein required for hedgehog signalling
Nature
Ptch2, a second mouse Patched gene is co-expressed with Sonic hedgehog
Nat. Genet.
Drosophila CBP is a co-activator of cubitus interruptus in hedgehog signalling
Nature
Gli1 is a target of Sonic hedgehog that induces ventral neural tube development
Development
A binding site for Gli proteins is essential for HNF-3 beta floor plate enhancer activity in transgenics and can respond to Shh in vitro
Development
Strike three for GLI3
Nat. Genet.
Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function
Nature
Holoprosencephaly: from Homer to hedgehog
Clin. Genet.
Cited by (0)
- 1
MD, PhD, Assistant Professor of Pediatrics
- 2
MD, PhD, Special Expert
- 3
MD, Associate Professor of Pediatrics and Genetics