Inpp5e Is Critical for Photoreceptor Outer Segment Maintenance

Area of Science:

• Ophthalmology
• Cell Biology
• Genetics

Background:

• Mutations in inositol polyphosphate-5-phosphatase e (INPP5E) are linked to human retinal degeneration, including Joubert and MORM syndromes and non-syndromic blindness.
• In mouse models, INPP5E deficiency results in various anomalies and impaired photoreceptor outer segment formation.

Purpose of the Study:

• To investigate the specific role of Inpp5e in photoreceptor outer segment development and maintenance.
• To elucidate the cellular mechanisms underlying Inpp5e-dependent photoreceptor integrity.

Main Methods:

• Generation of conditional and inducible mouse knockouts for Inpp5e in photoreceptors.
• Analysis of photoreceptor morphology, outer segment structure, Golgi apparatus, protein localization, and actin network dynamics.
• Assessment of extracellular vesicle formation and disc morphogenesis.

Main Results:

• Loss of Inpp5e in photoreceptors, regardless of timing, caused severe outer segment defects and photoreceptor cell loss.
• Key defects included outer segment shortening, reduced new disc formation, Golgi abnormalities, rhodopsin mislocalization, and extracellular vesicle accumulation.
• Reduced actin network and abnormal membrane whorl formation were observed in knockout cells.

Conclusions:

• Inpp5e is essential for maintaining photoreceptor outer segment structure and function.
• The enzyme plays a critical role in the continuous renewal process of photoreceptor outer segments.
• Dysfunction of Inpp5e disrupts normal disc morphogenesis and leads to photoreceptor degeneration.