Meis2 is required for GABAergic amacrine cell survival in the developing retina.

Amacrine cells (ACs) are the most diverse neuron in the retina, with more than sixty different subtypes, each contributing to the detection of specific visual features. Despite their importance in visual feature detection, the genetic basis for this diversity is still not well understood. Recent single-cell transcriptomic datasets have identified several potential genes that may regulate cellular diversity, but the underlying mechanisms have not been investigated. For example, the transcription factor Meis2 is selectively expressed in the GABAergic subclass of ACs. In this study, we focused on how Meis2 regulates the development of GABAergic ACs. We hypothesized that Meis2 is required for specification and survival of GABAergic ACs. To test this, we used the Meis2 conditional knockout mouse (Meis2-CKO) where Meis2 was deleted from either the entire retina or specifically from AC precursor cells. The deletion of Meis2 led to a ~60% reduction in total GABAergic ACs in the retina. This loss of GABAergic ACs occurred only after postnatal day 5 (P5), suggesting Meis2 is not required for early specification but may be required for survival. To further investigate cell death and survival, we quantified cleaved caspase-3 positive cells in the retina at several developmental timepoints. In Meis2-CKO mice, we found an increase in cleaved caspase-3 immunolabeling at P5 and P6 timepoints coinciding with the reduction of GABAergic ACs. Further analysis of GABAergic AC subtypes demonstrated a subtype-specific cell death in Meis2-CKO retinas. For example, the total number of dopaminergic (TH) ACs were significantly reduced, whereas starburst (ChAT) ACs remained unchanged. These findings suggest that Meis2 is important for the survival of a subset of GABAergic AC subtypes in the mammalian retina. In addition, Meis2 may control the expression of specific survival factors that prevent apoptosis during developmental cell death in the retina.