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Melody Shi, Oluwaseyi Motajo, Sumit Kumar, Tudor C. Badea; Genetic Interactions Between Brn3 Transcription Factors In Retinal Ganglion Cell Type Specification. Invest. Ophthalmol. Vis. Sci. 2011;52(14):6020.
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Retinal Ganglion Cells (RGCs) are a diverse group of neurons consisting of about 20 distinct cell types, which convey visual information via distinct channels to the brain. The developmental mechanisms by which distinct cell types acquire their very different dendritic arbor shapes and sizes and their specific axonal targeting to the different retinorecipient nuclei of the brain are largely unexplored.During early RGC development, the Brn3 family of transcription factors helps specify RGCs, by instructing various aspects of dendrite and axon formation. Previous published results suggest that Brn3b functions upstream of Brn3a and Brn3c and works to ensure both RGC survival and Brn3a and Brn3c expression. Brn3a is believed to be able to substitute for Brn3b when it is expressed from the Brn3b locus, and double mutants of Brn3c and Brn3b show more severe RGC loss than Brn3b single mutants. More recently, we reported that Brn3a may play a role in the specification of RGCs with a particular set of arbor morphologies. In addition, we also determined that Brn3a, Brn3b and Brn3c are expressed in overlapping, but not identical sets of adult RGC cell types. Taken together, these results raise the possibility that Brn3 transcription factors are part of a combinatorial code that regulates the formation of distinct RGC cell types. To explore the genetic interactions between the three transcription factors, we generated pair wise double-knockout combinations.
Here we describe genetic interactions between Brn3a and Brn3b with respect to their role in RGC formation.Retinas and brains from adult mice of a) Pax6αCre; Brn3b -/-; Brn3a CKOAP/+ b) Pax6αCre; Brn3b +/-; Brn3a CKOAP/+ c) Pax6αCre; Brn3b -/-; Brn3a CKOAP/- and d) Pax6αCre; Brn3b +/-; Brn3a CKOAP/- genotypes were analyzed by Alkaline Phosphatase histochemistry and indirect immunofluorescence.
We find that deleting Brn3b dramatically reduces but does not completely remove Brn3a positive RGCs from the retina and that surviving Brn3aAP/- RGCs exhibit abnormal dendritic arbor morphologies. In Brn3b-/-; Brn3aAP/- retinas, essentially no Brn3aAP RGCs can be seen, however some AP negative, Neurofilament positive RGCs survive.
We conclude that Brn3b is not required for Brn3a expression nor for the survival of Brn3a positive RGCs in a significant fraction of Brn3aAP RGCs, and that Brn3a has additional, Brn3b independent roles in RGC development and survival. These results are consistent with a combinatorial code hypothesis, in which various combinations of Brn3 transcription factors help to specify distinct RGC cell types.
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