Human developmental disorders and the Sonic hedgehog pathway

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Abstract

Sonic hedgehog (Shh) is a morphogen that is crucial for normal development of a variety of organ systems, including the brain and spinal cord, the eye, craniofacial structures, and the limbs. Mutations in the human SHH gene and genes that encode its downstream intracellular signaling pathway cause several clinical disorders. These include holoprosencephaly (HPE, the most common anomaly of the developing forebrain), nevoid basal cell carcinoma syndrome, sporadic tumors, including basal cell carcinomas, and three distinct congenital disorders: Greig syndrome Pallister–Hall syndrome, and isolated postaxial polydactyly. These conditions caused by abnormalities in the SHH pathway demonstrate the crucial role of SHH in complex developmental processes, and molecular analyses of these disorders provide insight into the normal function of the SHH pathway in human development.

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

  • 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?

  • 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)?

  • 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.

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  • Cited by (0)

    1

    MD, PhD, Assistant Professor of Pediatrics

    2

    MD, PhD, Special Expert

    3

    MD, Associate Professor of Pediatrics and Genetics

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