Hedgehog Signalling Flashcards
Cell behaviour links gene action & developmental processes
The past and current patterns of gene activity confer a certain state, or identity, on a cell at any given time, which is reflected in its molecular organisation-in particular which proteins are present.
Intracellular signalling is central to pattern formation
The French flag model: Signal X diffuses across field creating a gradient of concentration
Cells in field respond to different concentrations of X by turning on different genes.
Describe how hedgehog protein confers influence on neighboring cells
The hedghehog protein is a crucial signalling molecule that plays a significant role in the development and patterning of cells and tissues during embryonic development.
It exerts its influence on neighboring cells through a complex pathway known as the hedghehog signalling pathway.
Production & secretion of Hh
Hedgehog proteins are synthesized inside cells as precursor molecules. They undergo various modifications, including lipidation which allows them to attatch to the cell membrane.
Once lipidated, the Hh proteins are cleaved and released from the cell membrane to become active signalling molecules.
Reception by receptor cells
Hh proteins diffuse through extracellular space to reach neighboring cells. These cells express a receptor called Patched on their surface, which serves as the primary receptor for Hh signalling. When a Hh protein binds to Patched, it relieves the inhibitory effect of Patched on another transmembrane protein known as Smoothened.
Smoothened
Inactive Smoothened protein holds the transcription factor Cubitus interruptus (Ci) in a complex with a protein suppressor of fused (Su(fu))
In the absence of Hh, the Smoothened complex is also phosphorylated by several protein kinases (Glycogen synthase kinase GSK3, Protein Kinase A PKA, and Casein Kinase 1 CK1) which results in proteolytic cleavage of Ci and the formation of the truncated protein Ci Rep. CiRep inhibits Hh target gene expression.
Activation of the signalling pathway
Upon relief of Patched inhibition, Smoothened is activated and initiates a signalling cascade within the receiving cell. Ci is therefore released and acts as an activation transcription factor for target genes such as Wingless (wg) and decapentaplegic (dpp).
This leads to the activation of transcription factors called glioma-associated oncogene (Gli) proteins, which are key effectors of Hh signalling.
Gli protein regulation
Gli proteins can exist in three states: full-length activator form (GliA), truncated repressor form (GliR) and a cytoplasmic form (GliC). In the absence of Hh signalling, Gli proteins are proteolytically processed into GliR and GliC forms, which repress target gene expression. However, when Hh signalling is active, Gli proteins are phosphorylated and stabilized, promoting the formation of GliA, which acts as a transcriptional activator.
Gene expression regulation
GliA translocates to the nucleus and binds to specific DNA sequences in the regulatory regions of target genes that are involved in cell differentiation, proliferation and tissue patterning. These target geens can vary depending on the cell typr and context, allowing Hh signalling to exert specific effects on neighbouring cells.
