Abstract
BackgroundVisual information is conveyed from the retina to the brain via 15–20 Retinal Ganglion Cell (RGC) types. The developmental mechanisms by which RGC types acquire their distinct molecular, morphological, physiological and circuit properties are essentially unknown, but may involve combinatorial transcriptional regulation. Brn3 transcription factors are expressed in RGCs from early developmental stages, and are restricted in adults to distinct, partially overlapping populations of RGC types. Previously, we described cell autonomous effects of Brn3b (Pou4f2) and Brn3a (Pou4f1) on RGC axon and dendrites development.Methods and FindingsWe now have investigated genetic interactions between Brn3 transcription factors with respect to RGC development, by crossing conventional knock-out alleles of each Brn3 gene with conditional knock-in reporter alleles of a second Brn3 gene, and analyzing the effects of single or double Brn3 knockouts on RGC survival and morphology. We find that Brn3b loss results in axon defects and dendritic arbor area and lamination defects in Brn3a positive RGCs, and selectively affects survival and morphology of specific Brn3c (Pou4f3) positive RGC types. Brn3a and Brn3b interact synergistically to control RGC numbers. Melanopsin positive ipRGCs are resistant to combined Brn3 loss but are under the transcriptional control of Isl1, expanding the combinatorial code of RGC specification.ConclusionsTaken together these results complete our knowledge on the mechanisms of transcriptional control of RGC type specification. They demonstrate that Brn3b is required for the correct development of more RGC cell types than suggested by its expression pattern in the adult, but that several cell types, including some Brn3a, Brn3c or Melanopsin positive RGCs are Brn3b independent.
Highlights
To understand how neuronal circuits function we need to understand the morphological, physiological, molecular and functional properties of the neurons they are made of
They demonstrate that Brn3b is required for the correct development of more Retinal Ganglion Cell (RGC) cell types than suggested by its expression pattern in the adult, but that several cell types, including some Brn3a, Brn3c or Melanopsin positive RGCs are Brn3b independent
Fairly complete characterizations have been achieved for several types of intrinsically photosensitive RGCs, which can detect light through their own specific opsin, Melanopsin (Opn4), and participate in the circuits for Circadian Photoentrainment, and Pupillary Light Reflex [7,8,9,10,11,12]. ipRGCs [10,13] do not express either Brn3a or Brn3c [8,14], and a subpopulation of the M1 ipRGCs which projects to the Suprachiasmatic Nucleus (SCN), is Brn3b negative and survives deletion of the Brn3b gene or ablation of Brn3b positive RGCs [8,15]
Summary
To understand how neuronal circuits function we need to understand the morphological, physiological, molecular and functional properties of the neurons they are made of. A good example are Retinal Ganglion Cell (RGC) types, which convey features of visual information (luminosity, color, contrast, motion, etc.) via around 20 distinct parallel channels, to specific retinorecipient nuclei in the brain [1,2,3,4,5,6]. Genetic lines have helped correlate dendritic morphologies, physiological light responses, axonal projections to distinct brain nuclei and in some cases circuit functions for motion sensitive RGCs [15,16,17,18,19,20,21]. The developmental mechanisms by which RGC types acquire their distinct molecular, morphological, physiological and circuit properties are essentially unknown, but may involve combinatorial transcriptional regulation. We described cell autonomous effects of Brn3b (Pou4f2) and Brn3a (Pou4f1) on RGC axon and dendrites development
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