Lim1 Is Essential for the Correct Laminar Positioning of Retinal Horizontal Cells

Abstract

Although much is known about the transcriptional regulation that coordinates retinal cell fate determination, very little is known about the developmental processes that establish the characteristic laminar architecture of the retina, in particular, the specification of neuronal positioning. The LIM class homeodomain transcription factor Lim1 (Lhx1) is expressed in postmitotic, differentiating, and mature retinal horizontal cells. We show that conditional ablation of Lim1 results in the ectopic localization of horizontal cells to inner aspects of the inner nuclear layer, among the retinal amacrine cells. The ectopic cells maintain a molecular phenotype consistent with horizontal cell identity; however, these neurons adopt a unique morphology more reminiscent of amacrine cells, including a dendritic arbor positioned within the inner plexiform layer. All other retinal cell populations appear unaltered. Our data suggest a model whereby Lim1 lies downstream of horizontal cell fate determination factors and functions cell autonomously to instruct differentiating horizontal cells to the appropriate laminar position in the developing retina. This study is the first to describe a cell type-specific genetic program that is essential for targeting a discrete retinal neuron population to the proper lamina.

Transcription Factor Lim1 Specifies Horizontal Cell Laminar Position in the Retina

“…Importantly, Lim1 expression first becomes noticeable at embryonic day 14.5 (E14.5), when HC genesis is largely complete, suggesting that Lim1 labels differentiating, postmitotic HCs. The authors further confirm this observation by costaining embryonic retinal sections for Lim1 and a cell cycle marker, Ki67, and finding no overlap between these two markers [Poché et al (2007) flox allele together with retinaspecific Cre-expressing lines. In combination with this conditional allele, the authors used a Lim-1 lac-Z null allele to trace Lim-1-expressing cells.…”

“…Overall, the study by Poché et al (2007) is the first study clearly implicating a transcription factor in retinal lamination. Given that a number of other Lhx family members are expressed in the retina (Zhang et al, 2006), it is tempting to speculate that there exists an LIM transcription factor code specifying lamination throughout the retina and possibly elsewhere in the brain.…”

“…Whereas Lim1 is widely expressed in the developing and adult CNS, its expression pattern in the retina is restricted to differentiating and mature HCs [Poché et al (2007), their Fig. 1A-H (http://www.jneurosci.org/cgi/content/full/ 27/51/14099/F1)].…”

“…In the mutant Lim-1 retinas, lacZϩ cells were not restricted to the outer plexiform layer, as is seen in the wild-type situation. Instead, a large proportion of lacZϩ cells was observed to project into the inner plexiform layer and stratify adjacent to the ganglion cell layer [Poché et al (2007) Because the ectopic lacZϩ cells localize to the amacrine cell layer and take on amacrine-like morphology, one might wonder whether their molecular identity has also been disrupted. The authors address this question with an extensive panel of markers that have traditionally been used to characterize HCs and other cellular populations within the retina.…”

“…The authors address this question with an extensive panel of markers that have traditionally been used to characterize HCs and other cellular populations within the retina. The authors find that the ectopic lacZϩ cells display a molecular "signature" that is consistent only with the HC fate [Poché et al (2007) To gain more insight into the mechanism by which Lim1 affects HC positioning, the authors performed a time course of the mutant HC migration [Poché et al (2007), their Fig. 6 (http://www.…”