Genetic modulation of horizontal cell number in the mouse retina

Abstract

Neuronal populations display conspicuous variability in their size among individuals, but the genetic sources of this variation are largely undefined. We demonstrate a large and highly heritable variation in neuron number within the mouse retina, affecting a critical population of interneurons, the horizontal cells. Variation in the size of this population maps to the distal end of chromosome (Chr) 13, a region homologous to human Chr 5q11.1–11.2. This region contains two genes known to modulate retinal cell number. Using conditional knock-out mice, we demonstrate that one of these genes, the LIM homeodomain gene Islet-1 ( Isl1 ), plays a role in regulating horizontal cell number. Genetic differences in Isl1 expression are high during the period of horizontal cell production, and cis -regulation of Isl1 expression within the retina is demonstrated directly. We identify a single nucleotide polymorphism in the 5′ UTR of Isl1 that creates an E-box sequence as a candidate causal variant contributing to this variation in horizontal cell number.

Expression and function of the LIM-homeodomain transcription factor Islet-1 in the developing and mature vertebrate retina

“…4). Thus, the absence of Isl1 during retinal development results in variations in the number of ganglion, amacrine, bipolar, and horizontal cells (Elshatory et al, 2007b;Whitney et al, 2011). It has been shown that retinal cell fate determination and differentiation are controlled by intrinsic cues, such as transcription factors, and extrinsic signals, such as neurotrophic factors.…”

“…2C, JeL) (Elshatory et al, 2007a;Poche et al, 2007). Surprisingly, Whitney et al (2011), using conditional knockout mice, demonstrate that Isl1 plays a key role in regulating horizontal cell numbers. In particular, there is a substantial increase in horizontal cells in the knockout retina with drastically reduced numbers of ganglion, cholinergic amacrine, and bipolar cells.…”

“…Because Isl1-null mice die at E10.5, before the onset of retinal neurogenesis (Pfaff et al, 1996), the role of Isl1 in retinogenesis is poorly understood. However, recent studies have shown that its conditional deletion in the developing retina induces variations in the numbers of ganglion, cholinergic amacrine, bipolar, and horizontal cells (Elshatory et al, 2007b;Mu et al, 2008;Pan et al, 2008;Whitney et al, 2011). Furthermore, some authors have described a transient expression Korzh et al, 1993 Onset of Isl1 immunoreactivity in the retina -Isl1-immunoreactive neurons appear after 24hpf.…”

Deterioration of the Medial Olivocochlear Efferent System Accelerates Age-Related Hearing Loss in Pax2-Isl1 Transgenic Mice

“…Embryos lacking the Isl1 gene die by embryonic day E10.5, indicating an essential requirement for ISL1 during normal embryonic development [14]. Lossof-function studies in the mouse have revealed crucial roles for ISL1 in motor neuron, pancreatic, cardiac, and eye development [15][16][17][18][19]. Thus, ISL1 contributes to the development of neuronal and non-neuronal cell types, suggesting that its activity is context dependent.…”

“…Thus, ISL1 contributes to the development of neuronal and non-neuronal cell types, suggesting that its activity is context dependent. The dose-dependent requirement for Isl1 is an interesting aspect of ISL1 regulation, which affects the specification of motor neurons [20] and modulates horizontal cell number in the mouse retina [19]. During normal ear development, ISL1 appears first in the otic placode and it is then upregulated in the cells that will form the cochleovestibular ganglion during placode invagination [21].…”