Islet-1 Controls the Differentiation of Retinal Bipolar and Cholinergic Amacrine Cells

Abstract

Whereas the mammalian retina possesses a repertoire of factors known to establish general retinal cell types, these factors alone cannot explain the vast diversity of neuronal subtypes. In other CNS regions, the differentiation of diverse neuronal pools is governed by coordinately acting LIM-homeodomain proteins including the Islet-class factor Islet-1 (Isl1). We report that deletion of Isl1 profoundly disrupts retinal function as assessed by electroretinograms and vision as assessed by optomotor behavior. These deficits are coupled with marked reductions in mature ON-and OFF-bipolar (Ͼ76%), cholinergic amacrine (93%), and ganglion (71%) cells. Mosaic deletion of Isl1 permitted a chimeric analysis of "wild-type" cells in a predominantly Isl1-null environment, demonstrating a cell-autonomous role for Isl1 in rod bipolar and cholinergic amacrine development. Furthermore, the effects on bipolar cell development appear to be dissociable from the preceding retinal ganglion cell loss, because Pou4f2-null mice are devoid of similar defects in bipolar cell marker expression. Expression of the ON-and OFF-bipolar cell differentiation factors Bhlhb4 and Vsx1, respectively, requires the presence of Isl1, whereas the early bipolar cell marker Prox1 initially did not. Thus, Isl1 is required for engaging bipolar differentiation pathways but not for general bipolar cell specification. Spatiotemporal expression analysis of additional LIM-homeobox genes identifies a LIMhomeobox gene network during bipolar cell development that includes Lhx3 and Lhx4. We conclude that Isl1 has an indispensable role in retinal neuron differentiation within restricted cell populations and this function may reflect a broader role for other LIM-homeobox genes in retinal development, and perhaps in establishing neuronal subtypes.

Islet 1 specifies the identity of hypothalamic melanocortin neurons and is critical for normal food intake and adiposity in adulthood

“…Mice were housed in ventilated cages under controlled temperature and photoperiod (12- (27) were obtained from L. Gan, University of Rochester, Rochester, NY, and maintained in our laboratory as homozygotes on a mixed background. CAAG-CreERT mice (28) were obtained from The Jackson Laboratory (B6.Cg-Tg[CAG-cre/Esr1]5Amc/J) and were intercrossed with Isl1 loxP/loxP mice to generate the TAM-inducible Isl1 conditional knockout strain CAG-CreERT.Isl1 loxP/loxP .…”

“…To examine this possibility, we sought to analyze Pomc expression in mice deficient in Isl1. Because Isl1 −/− mouse embryos die at E9.5 due to impaired vascular development (26), we used Isl1 loxP/loxP mice that carry two loxP sites flanking the critical exon 2 (27) in combination with mice ubiquitously expressing a tamoxifen (TAM)-inducible Cre recombinase (CAAG-CreERT) (28). Pregnant Isl1 loxP/loxP dams previously crossed with Isl1 loxP/loxP .CAAG-CreERT male mice were injected at E9.5 with TAM to generate Isl1KO@E9.5 embryos that were analyzed 2 d later (Fig.…”

Histone demethylase Jmjd3 is required for the development of subsets of retinal bipolar cells

“…However, this was difficult to confirm, given the lack of a specific marker for this BP subset. Furthermore, although Isl1 is strictly expressed in the ON-BP subset in the mature retina (21,22,26), Isl1-KO mice also have OFF-BP subset defects, suggesting that Isl1 is transiently expressed in OFF-BP cell precursors (27) and that the precursors of Recoverin-positive cells are found in the Isl1-positive fractions. The level of H3K27me3 at the Cdkn2a (Ink4a) locus was not significantly different between the Isl1-positive and Isl1-negative populations, and that at the Elavl3 locus was slightly higher in Isl1-positive cells.…”

Islet1 selectively promotes peripheral axon outgrowth in Rohon‐Beard primary sensory neurons

“…Isl1 is expressed in motor and retinal neurons of the central nervous system (CNS) and in various types of sensory neurons, including neurons of the dorsal root and cranial ganglia (Appel et al, 1995;Elshatory et al, 2007;Hutchinson and Eisen, 2006;Pfaff et al, 1996;Sun et al, 2008;Thaler et al, 2002Thaler et al, , 2004Tsuchida et al, 1994;Uemura et al, 2005). In mice, isl1-deficient embryos die before sensory neuron maturation (Pfaff et al, 1996).…”