title: Genetic interactions between Brn3 transcription factors in retinal ganglion cell type specification.
abstract: BACKGROUND
  Visual 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.
  
  
  RESULTS
  We 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.
  
  
  CONCLUSIONS
  Taken 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.
authors.affiliation: National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Melody
authors.initials: M
authors.lastname: Shi
authors.forename: Sumit R
authors.initials: SR
authors.lastname: Kumar
authors.forename: Oluwaseyi
authors.initials: O
authors.lastname: Motajo
authors.forename: Friedrich
authors.initials: F
authors.lastname: Kretschmer
authors.forename: Xiuqian
authors.initials: X
authors.lastname: Mu
authors.forename: Tudor C
authors.initials: TC
authors.lastname: Badea
mesh_terms: D000818:Animals; D002452:Cell Count; D002470:Cell Survival / Q000235:genetics; D004843:Epistasis, Genetic; D005260:Female; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D016900:Neurofilament Proteins / Q000378:metabolism; D012160:Retina / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000166:cytology / Q000378:metabolism*; D017299:Rod Opsins / Q000378:metabolism; D050819:Transcription Factor Brn-3A / Q000235:genetics* / Q000378:metabolism; D050820:Transcription Factor Brn-3B / Q000235:genetics* / Q000378:metabolism; D050821:Transcription Factor Brn-3C / Q000235:genetics* / Q000378:metabolism; D000099210:Melanopsin
chemical_list: D018398:Homeodomain Proteins; D016900:Neurofilament Proteins; D017299:Rod Opsins; D050819:Transcription Factor Brn-3A; D050820:Transcription Factor Brn-3B; D050821:Transcription Factor Brn-3C; D000099210:Melanopsin; C494189:Pou4f1 protein, mouse; C085559:Pou4f2 protein, mouse; C044882:neurofilament protein L