A targeting mutation of tyrosine 1062 in Ret causes a marked decrease of enteric neurons and renal hypoplasia

Area of Science:

• Developmental Biology
• Molecular Biology
• Genetics

Background:

• The Ret receptor tyrosine kinase is vital for enteric nervous system and kidney development.
• Tyrosine 1062 in Ret is a key binding site for signaling proteins activating pathways like RAS/ERK and PI3K/AKT.
• Understanding Ret's signaling role is crucial for organogenesis research.

Purpose of the Study:

• To investigate the in vivo importance of Ret's tyrosine 1062 for organogenesis.
• To elucidate the specific roles of Ret signaling in the enteric nervous system and kidney development.

Main Methods:

• Generation of knock-in mice with tyrosine 1062 in Ret replaced by phenylalanine.
• Phenotypic analysis of homozygous mutant mice, including survival, growth, enteric nervous system development, and kidney morphology.
• Histological examination of enteric ganglia and kidney tissues.

Main Results:

• Homozygous knock-in mice exhibited growth retardation and died by postnatal day 27.
• Severe enteric nervous system defects were observed, with ~40% lacking enteric neurons and others showing reduced ganglion cell size and number.
• Kidney development was impaired, showing reduced size due to decreased ureteric bud branching, though less severe than in Ret-deficient mice.

Conclusions:

• Ret signaling via tyrosine 1062 is essential for proper enteric nervous system histogenesis.
• Tyrosine 1062 plays a significant role in nephrogenesis, specifically in ureteric bud branching during kidney development.
• These findings highlight the critical function of Ret's tyrosine 1062 in the development of multiple organ systems.