Context-dependent compensation among phosphatidylserine-recognition receptors

Area of Science:

• Immunology
• Cell Biology
• Ophthalmology

Background:

• Phagocytes utilize multiple phosphatidylserine (PtdSer) receptors to recognize and clear apoptotic cells.
• The specific roles and interchangeability of these PtdSer receptors in vivo remain largely unknown.
• Loss of MerTK, a key PtdSer receptor, leads to apoptotic cell accumulation in testes and photoreceptor degeneration in the eye due to impaired phagocytosis.

Purpose of the Study:

• To investigate whether the PtdSer receptor BAI1 can compensate for the loss of MerTK in vivo.
• To determine the tissue-specific functional differences between MerTK and BAI1 in apoptotic cell clearance.
• To elucidate the molecular mechanisms underlying MerTK's critical role in retinal pigmented epithelium (RPE) function.

Main Methods:

• Overexpression of the PtdSer receptor BAI1 in MerTK-deficient (Mertk-/-) mice (Mertk-/- Bai1Tg).
• Assessment of apoptotic germ cell clearance in testes and photoreceptor degeneration in the eye.
• Analysis of visual cycle intermediates and unbiased RNA sequencing (RNAseq) of RPE from Mertk+/+ and Mertk-/- mice.

Main Results:

• BAI1 overexpression rescued the clearance of apoptotic germ cells in the testes of Mertk-/- mice.
• BAI1 overexpression failed to rescue RPE phagocytosis or prevent photoreceptor degeneration in Mertk-/- mice.
• Mertk-/- mice exhibited dysregulation of genes involved in phagocytosis, metabolism, and retinal disease, even before photoreceptor degeneration onset.

Conclusions:

• Phagocytic receptors are not functionally interchangeable; their compensatory roles are context- and tissue-dependent.
• MerTK plays a critical, non-redundant role in RPE phagocytosis and retinal health.
• Dysregulation of specific gene networks in MerTK-deficient RPE contributes to photoreceptor degeneration.