Abstract
The Hedgehog (HH) signalling pathway is one of the major pathways controlling cell differentiation and proliferation during human development. This pathway is complex, with HH function influenced by inhibitors, promotors, interactions with other signalling pathways, and non-genetic and cellular factors. Many aspects of this pathway are not yet clarified. The main features of Sonic Hedgehog (SHH) signalling are discussed in relation to its function in human development. The possible role of SHH will be considered using examples of holoprosencephaly and short-rib polydactyly (SRP) syndromes. In these syndromes, there is wide variability in phenotype even with the same genetic mutation, so that other factors must influence the outcome. SHH mutations were the first identified genetic causes of holoprosencephaly, but many other genes and environmental factors can cause malformations in the holoprosencephaly spectrum. Many patients with SRP have genetic defects affecting primary cilia, structures found on most mammalian cells which are thought to be necessary for canonical HH signal transduction. Although SHH signalling is affected in both these genetic conditions, there is little overlap in phenotype. Possible explanations will be canvassed, using data from published human and animal studies. Implications for the understanding of SHH signalling in humans will be discussed.
Highlights
South Eastern Area Laboratory Services, Department of Anatomical Pathology, NSW Health Pathology, Prince of Wales Hospital, Sydney, NSW 2031, Australia
This review focuses on Sonic Hedgehog (SHH) and SHH signalling; downstream of the HH ligand, the molecular mechanisms of HH signalling are largely conserved; downstream aspects of SHH signalling apply to HH signalling in general [2]
Studies in mice show that Gas1, Cdon and Boc expression vary in time and spatial distribution and may regulate HH expression [15]
Summary
The Hedgehog (HH) signalling pathway is one of the major pathways controlling cell patterning, differentiation and proliferation during human development. SHH isand secreted in sites with activity, forwith example, in the notochord and the floorplate, neural tube notochord inorganising early embryos, later defects observed prechordal mesoderm, spreading to the overlying tubecell and patterns its dorsovenin the distal limb structures, cyclopia, abnormalities of neural ventral types of the neural tral axis. SHH morphogen is produced by cells in the zone of tube, absent spinal polarising column activity and most ribsbud [7].and. These polypeptides areaxis transported (ZPA)of in the the limb patterns the anteroposterior of the limb to. SHH that has already been secreted can be recycled into the cell, transported to microvesicular bodies where they can be packaged into extracellular vesicles for secretion (modified after [10])
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