Hand2 regulates extracellular matrix remodeling essential for gut-looping morphogenesis in zebrafish

Area of Science:

• Developmental Biology
• Molecular Biology
• Cell Biology

Background:

• Extracellular matrix (ECM) remodeling is crucial for organogenesis, but its molecular regulation remains unclear.
• Asymmetric migration of the lateral plate mesoderm (LPM) in zebrafish is vital for correct organ positioning, including the liver and pancreas.

Purpose of the Study:

• To investigate the molecular mechanisms regulating LPM migration during zebrafish organogenesis.
• To elucidate the role of the transcription factor Hand2 in ECM remodeling and its impact on gut looping.

Main Methods:

• Transgenic zebrafish expressing EGFP under the control of Hand2 regulatory sequences were generated for cellular resolution imaging.
• Laminin distribution and matrix metalloproteinase (MMP) activity were assessed during LPM migration.
• The effects of Hand2 loss-of-function on LPM migration and ECM deposition were analyzed.

Main Results:

• Laminin was observed along the LPM/gut boundary and diminished by migrating Hand2-expressing cells.
• Laminin diminishment, dependent on MMP activity, is necessary for LPM migration.
• Loss of Hand2 function led to reduced MMP activity, sustained laminin deposition, and impaired asymmetric LPM migration and gut looping.

Conclusions:

• Hand2 plays a critical role in modulating ECM remodeling through MMP activity during organogenesis.
• This study reveals an unexpected function for Hand2 in regulating ECM remodeling essential for zebrafish gut looping and organ placement.