Abstract
Since its initial discovery in a Drosophila mutagenesis screen, the Hedgehog pathway has been revealed to be instrumental in the proper development of the vertebrate face. Vertebrates possess three hedgehog paralogs: Sonic hedgehog (Shh), Indian hedgehog (Ihh), and Desert hedgehog (Dhh). Of the three, Shh has the broadest range of functions both in the face and elsewhere in the embryo, while Ihh and Dhh play more limited roles. The Hedgehog pathway is instrumental from the period of prechordal plate formation early in the embryo, until the fusion of the lip and secondary palate, which complete the major patterning events of the face. Disruption of Hedgehog signaling results in an array of developmental disorders in the face, ranging from minor alterations in the distance between the eyes to more serious conditions such as severe clefting of the lip and palate. Despite its critical role, Hedgehog signaling seems to be disrupted through a number of mechanisms that may either be direct, as in mutation of a downstream target of the Hedgehog ligand, or indirect, such as mutation in a ciliary protein that is otherwise seemingly unrelated to the Hedgehog pathway. A number of teratogens such as alcohol, statins and steroidal alkaloids also disrupt key aspects of Hedgehog signal transduction, leading to developmental defects that are similar, if not identical, to those of Hedgehog pathway mutations. The aim of this review is to highlight the variety of roles that Hedgehog signaling plays in developmental disorders of the vertebrate face.
Highlights
Developmental disorders of the craniofacial region are among the most common birth defects in humans, and the Hedgehog (Hh) signaling pathway is often intimately involved
The Drosophila hedgehog gene has evolved into three paralogs: Sonic hedgehog (Shh), Indian hedgehog (Ihh), and Desert hedgehog (Dhh) [21,26]
Shh is the only vertebrate Hh homolog expressed in the central nervous system [111,112], and its disruption is well documented to result in a range of craniofacial abnormalities having to do with the midline of the head [107,110,113]
Summary
Developmental disorders of the craniofacial region are among the most common birth defects in humans (cleft lip and palate have a prevalence of ~1:700 births [1,2]), and the Hedgehog (Hh) signaling pathway is often intimately involved. The Hh pathway has long been implicated in a number of roles during embryonic development, including neural crest cell survival [4], left-right asymmetry [5,6], anteroposterior patterning of limbs [7,8], dorsoventral patterning of somites [9], as well as the development of the eyes [10,11,12], bone [13], cartilage [14,15], gonads and germ cells [16], muscle [17,18,19,20], nervous system [21,22,23], and teeth [24,25]. Expression patterns and functions differ spatiotemporally across the three vertebrate Hh paralogs
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