Abstract
Programmed cell death is widespread during the development of the central nervous system and serves multiple purposes including the establishment of neural connections. In the mouse retina a substantial reduction of retinal ganglion cells (RGCs) occurs during the first postnatal week, coinciding with the formation of retinotopic maps in the superior colliculus (SC). We previously established a retino-collicular culture preparation which recapitulates the progressive topographic ordering of RGC projections during early post-natal life. Here, we questioned whether this model could also be suitable to examine the mechanisms underlying developmental cell death of RGCs. Brn3a was used as a marker of the RGCs. A developmental decline in the number of Brn3a-immunolabelled neurons was found in the retinal explant with a timing that paralleled that observed in vivo. In contrast, the density of photoreceptors or of starburst amacrine cells increased, mimicking the evolution of these cell populations in vivo. Blockade of neural activity with tetrodotoxin increased the number of surviving Brn3a-labelled neurons in the retinal explant, as did the increase in target availability when one retinal explant was confronted with 2 or 4 collicular slices. Thus, this ex vivo model reproduces the developmental reduction of RGCs and recapitulates its regulation by neural activity and target availability. It therefore offers a simple way to analyze developmental cell death in this classic system. Using this model, we show that ephrin-A signaling does not participate to the regulation of the Brn3a population size in the retina, indicating that eprhin-A-mediated elimination of exuberant projections does not involve developmental cell death.
Highlights
During the development of the central nervous system, neurogenesis and programmed cell death occur concomitantly
With the decline of Brn3a-expressing retinal ganglion cells (RGCs), retinal surface increased, and, the RGC layer of the retina reorganized into a single cell layer (Fig. 1A)
To evaluate whether reduction in cell number was a general feature of all retinal cell types during the first post-natal week, retinal sections were stained for recoverin, a marker for photoreceptors [23], or choline acetyltransferase (ChAT), a marker for starburst amacrine cells [24,25], a subpopulation of interneurons in the inner nuclear layer
Summary
During the development of the central nervous system, neurogenesis and programmed cell death occur concomitantly. Developmental cell death plays different roles in morphogenesis: regulation of the size of progenitor population in the CNS, removal of damaged cells, optimization of cell population matching between interconnected neurons and removal of neurons with ectopic connections [1]. The main wave of histogenetic cell death occurs during the first two postnatal weeks, coinciding with the formation of retinotopic maps in the superior colliculus (SC). All retinal cell types undergo developmental cell death, with different time-courses [2,3] but retinal ganglion cells (RGCs) are the ones undergoing substantial developmental cell death. While 5% of the photoreceptors undergo developmental cell death, up to 50% of RGCs are lost due to cell death, peaking between P2 and P4 in mice [3,4]. The methods used to quantify the reduction in RGC number have often been indirect, and have led to a large variability in the results, ranging from 9% [3] to 90% [5]
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