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Review
. 2017 Mar 13;5(1):3.
doi: 10.3390/jdb5010003.

Canonical Sonic Hedgehog Signaling in Early Lung Development

Hugo Fernandes-Silva  1   2 , Jorge Correia-Pinto  3   4   5 , Rute Silva Moura  6   7   8
Affiliations
Review

Canonical Sonic Hedgehog Signaling in Early Lung Development

Hugo Fernandes-Silva et al. J Dev Biol. .

Abstract

The canonical hedgehog (HH) signaling pathway is of major importance during embryonic development. HH is a key regulatory morphogen of numerous cellular processes, namely, cell growth and survival, differentiation, migration, and tissue polarity. Overall, it is able to trigger tissue-specific responses that, ultimately, contribute to the formation of a fully functional organism. Of all three HH proteins, Sonic Hedgehog (SHH) plays an essential role during lung development. In fact, abnormal levels of this secreted protein lead to severe foregut defects and lung hypoplasia. Canonical SHH signal transduction relies on the presence of transmembrane receptors, such as Patched1 and Smoothened, accessory proteins, as Hedgehog-interacting protein 1, and intracellular effector proteins, like GLI transcription factors. Altogether, this complex signaling machinery contributes to conveying SHH response. Pulmonary morphogenesis is deeply dependent on SHH and on its molecular interactions with other signaling pathways. In this review, the role of SHH in early stages of lung development, specifically in lung specification, primary bud formation, and branching morphogenesis is thoroughly reviewed.

Keywords: Sonic Hedgehog (SHH); branching morphogenesis; endoderm specification; lung development; signaling; transcriptional regulation.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Sonic hedgehog signaling pathway. (1) ON state: SHH protein binds to PTCH1 receptor, at the cell surface level. This event abolishes SMO inhibition that can move to the primary cilia to induce GLI activation through SUFU detachment. Then, GLI2A and GLI3A translocate to the nucleus in order to promote the transcription of target genes; GLI2A acts as the main activator. (2) OFF state: In the absence of SHH ligand, PTCH1 inhibits SMO, and GLIs are phosphorylated by PKA/CK1/GSK3 complex. GLI2R and GLI3R are formed and can follow two possible destinations: proteasome degradation or translocation into the nucleus to repress the transcription of targets genes. In this case, GLI3R is the major repressor.
Figure 2
Figure 2
Schematic representation of SHH main interactions during lung endoderm specification.
Figure 3
Figure 3
Schematic representation of SHH main interactions during lung endoderm specification.
See this image and copyright information in PMC

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