Differential and compensatory roles for type I phosphatidylinositol-4-phosphate-5-kinase isoforms in retinal function and health.

Phosphatidylinositol (4,5) bisphosphate (PI(4,5)P2) plays important roles in development, signaling, intracellular trafficking and regulation throughout the nervous system. Using selective and combined gene ablation strategies, we have determined the roles of this lipid and the kinase isoforms of the PIP5KI family primarily responsible for its synthesis in mouse retina. In rod cells, PI(4,5)P2 localizes predominantly to the plasma membrane of inner and outer segments and is enriched in membranes near the synaptic termini. Disruption of the gene encoding the {gamma} PIP5KI isoform, Pip5k1c, throughout the developing retina, using Cre expression driven by a Six3 transcription factor-dependent promoter, yields dramatic, but not complete, loss of the protein, with no apparent effects on morphology or function through the first 3-4 months after birth. Slowly progressing photoreceptor degeneration is observed at later ages. Complete loss of the {gamma} isoform in rods, driven by the rhodopsin promoter-based iCre75 transgene, leads to no obvious developmental defects, but results in an earlier-onset rod degeneration. Germ-line ablation of neither the Pip5k1a nor the Pip5k1b gene leads to any observable morphological defects. Homozygous Pip5k1a ablation leads to functional defects in photoreceptors as revealed by reduced a-wave and b-wave amplitudes in the electroretinograms. On the background of rod-specific Pip5k1c ablation, Pip5k1a deficiency greatly accelerates retinal degeneration. These results reveal a complex interplay among PIP5KI isoforms in ensuring proper photoreceptor function and health, with apparent partial redundancy in fulfilling their critical functions. They underscore the important role of PI(4,5)P2 in neuronal signaling and homeostasis. Significance StatementPhosphatidylinositol(4,5)P2, PI(4,5)P2, plays essential roles in nervous system development and function, but its roles in retina have been unknown. This study combines biochemistry, mouse genetics, light- and electron microscopy to reveal both specific and redundant functions for PIP2 formed by different kinase isoforms in the mammalian retina. It has implications for retinal function, disease and therapy, and for the broader field of phosphoinositide regulation.