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.
Highlights
The development of a fully functional organism is a result of a highly regulated process, orchestrated by several signaling pathways and countless interactions that compose an intricate molecular network
When the signaling pathway is “ON”, Sonic Hedgehog (SHH) binds to PTCH1 and releases SMO inhibition that can move to the primary cilia, an essential cellular structure for the transduction of HH signal in vertebrates that acts as a SHH sensor [24,25]
Zinc finger glioma-associated transcription factors (GLI) are transformed into their activator forms and dissociate from suppressor of fused (SUFU), a protein encoded by a tumor suppressor gene [26]
Summary
The development of a fully functional organism is a result of a highly regulated process, orchestrated by several signaling pathways and countless interactions that compose an intricate molecular network These signaling pathways sharply control pivotal cellular processes, such as cell survival, proliferation, differentiation, migration, and apoptosis, among others and, contribute to the formation of organs and systems. Lung development relies on continuous interactions between the epithelial and mesenchymal compartment, coordinated by numerous transcription and growth factors that, overall, contribute to the proper formation of the respiratory system [6] This developmental process requires the precise activation of several signaling cascades, namely, FGF (fibroblast growth factor), TGFβ-BMP (transforming growth factor β-bone morphogenetic protein), WNT (Wingless-related integration site), HIPPO, RA (retinoic acid), NOTCH, and SHH (Sonic Hedgehog) (reviewed by [7,8]).
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