Nfia Is Critical for AII Amacrine Cell Production: Selective Bipolar Cell Dependencies and Diminished ERG

• Published in: The Journal of neuroscience Vol. 43; no. 49; pp. 8367 - 8384
• Main Authors: Keeley, Patrick W, Trod, Stephanie, Gamboa, Bruno N, Coffey, Pete J, Reese, Benjamin E
• Format: Journal Article
• Language: English
• Published: United States Society for Neuroscience 06.12.2023
• Subjects: Amacrine cells; Amacrine Cells - metabolism; Animals; Bipolar cells; Cell differentiation; Cell fate; Cell number; Electroretinograms; Electroretinography; Female; Male; Mice; Neural stem cells; NFI Transcription Factors - metabolism; Nuclear factor I; Progenitor cells; Reduction; Retina; Retina - metabolism; Retinal Bipolar Cells; Retinal cells; Specifications; Transcription Factors - metabolism; electroretinogram; apoptosis; oscillatory potentials; differentiation; stratification; fate determination
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.1099-23.2023

The nuclear factor one (NFI) transcription factor genes , , and are all enriched in late-stage retinal progenitor cells, and their loss has been shown to retain these progenitors at the expense of later-generated retinal cell types. Whether they play any role in the specification of those later-generated fates is unknown, but the expression of one of these, , in a specific amacrine cell type may intimate such a role. Here, conditional knockout ( -CKO) mice (both sexes) were assessed, finding a massive and largely selective absence of AII amacrine cells. There was, however, a partial reduction in type 2 cone bipolar cells (CBCs), being richly interconnected to AII cells. Counts of dying cells showed a significant increase in -CKO retinas at postnatal day (P)7, after AII cell numbers were already reduced but in advance of the loss of type 2 CBCs detected by P10. Those results suggest a role for in the specification of the AII amacrine cell fate and a dependency of the type 2 CBCs on them. Delaying the conditional loss of to the first postnatal week did not alter AII cell number nor differentiation, further suggesting that its role in AII cells is solely associated with their production. The physiological consequences of their loss were assessed using the ERG, finding the oscillatory potentials to be profoundly diminished. A slight reduction in the b-wave was also detected, attributed to an altered distribution of the terminals of rod bipolar cells, implicating a role of the AII amacrine cells in constraining their stratification. The transcription factor NFIA is shown to play a critical role in the specification of a single type of retinal amacrine cell, the AII cell. Using an -conditional knockout mouse to eliminate this population of retinal neurons, we demonstrate two selective bipolar cell dependencies on the AII cells; the terminals of rod bipolar cells become mis-stratified in the inner plexiform layer, and one type of cone bipolar cell undergoes enhanced cell death. The physiological consequence of this loss of the AII cells was also assessed, finding the cells to be a major contributor to the oscillatory potentials in the electroretinogram.