Front. Genet., 08 November 2019

The hedgehog (Hh) family comprises sonic hedgehog (Shh), Indian hedgehog (Ihh), and desert hedgehog (Dhh), which are versatile signaling molecules involved in a wide spectrum of biological events including cell differentiation, proliferation, and survival; establishment of the vertebrate body plan; and aging. These molecules play critical roles from embryogenesis to adult stages

The Hh family involves many signaling mediators and functions through complex mechanisms, and achieving a comprehensive understanding of the entire signaling system is challenging.

The regulatory mechanisms of the Hh pathway are complex, and new mechanisms are continuously being identified. Because each new finding triggers another question, many researchers in various fields including molecular and cell biology, genetics, medicine, biochemistry, protein structure, chemistry, and mathematical biology have chosen Hh as the focus of their research.

Hh proteins are involved in a variety of biological events such as cell differentiation, proliferation, and survival. The fact that multiple processes that are apparently distinct from each other are induced by a single Hh protein should be addressed in the future. Future studies on Hh could focus on the cell type-specific expression levels of each mediator of the Hh signaling pathway. Although there are more than 30 mediators of Hh signaling, the expression levels of these proteins are likely cell type-specific, which may confer variation in the kinetics and responsiveness to the signal.

The mechanisms underlying the cell type specificity of target genes involved in the Hh signaling pathway should be investigated. Although most signaling mediators are common to Shh, Ihh, and Dhh, the downstream genes induced are context-dependent. This variation may be achieved through crosstalk with other signaling molecules, or differences in the transcription factors interacting with Gli or the epigenetic background (chromatin status) of cells. Even in the same neural progenitor cells, early and late progenitor cells show differential responses to the same Shh protein

Despite extensive research, many mechanisms underlying Hh signaling may remain undiscovered, and cutting-edge approaches, such as chasing single cells or single proteins, computational prediction, and genome-wide functional screens, are warranted to elucidate these mechanisms.