Diffusion barriers imposed by tissue topology shape morphogen gradients.

Area of Science:

• Developmental Biology
• Molecular Biology
• Evolutionary Biology

Background:

• Morphogen gradients are crucial for tissue development, but how their signaling range adapts to varying tissue sizes remains unclear.
• Animals utilize a limited set of morphogens for complex patterning, necessitating efficient regulatory mechanisms.

Approach:

• Employed single-molecule imaging in reconstituted gradients and tissue explants to analyze Hedgehog diffusion dynamics.
• Developed a novel topology-limited diffusion model to explain morphogen movement across cell-cell gaps.

Key Points:

• Hedgehog (Hh) diffuses extracellularly as a monomer, rapidly switching between membrane-confined and -unconfined states.
• Vertebrate protein SCUBE1 expands Hh gradients by accelerating state transition rates, not by altering molecular abundance.
• Existing diffusion models failed to explain SCUBE1's effect; the new model incorporates cell-cell gaps as diffusion barriers.

Conclusions:

• SCUBE1 facilitates Hh secretion and diffusion by enabling transient passage through membrane-unconfined states, overcoming topological barriers.
• This study presents a multiscale understanding of morphogen gradient formation, unifying prior models.
• Identified novel regulatory mechanisms (knobs) for tuning morphogen gradient sizes in development and evolution.