POU domain factor Brn-3b is essential for retinal ganglion cell differentiation and survival but not for initial cell fate specification.
While the mammalian retina is well understood at the anatomical and physiological levels, little is known about the mechanisms that give rise to the retina's highly ordered pattern or its diverse neuronal cell types. Previous investigations have shown that gene disruption of the POU-IV class transcription factor Brn-3b (Brn-3.2) resulted in the loss of most retinal ganglion cells in retinas of postnatal mice. Here, we used lacZ and human placental alkaline phosphatase genes knocked into the brn-3b locus to follow the fate of brn-3b-mutant cells in the developing retina. We found that Brn-3b was not required for the initial commitment of retinal ganglion cell fate or for the migration of ganglion cells to the ganglion cell layer. However, Brn-3b was essential for the normal differentiation of retinal ganglion cells; without it, the cells underwent enhanced apoptosis. Retinal ganglion cells lacking brn-3b extended processes at the appropriate time in development, but these processes were disorganized, resulting in a thinner optic nerve. Explanted retinas from brn-3b-null embryos also extended processes when cultured in vitro, but the processes were shorter and less bundled than in wild-type retinas. Ultrastructural and marker analyses showed that the processes of mutant ganglion cells had dendritic rather than axonal features, suggesting that mutant cells formed dendrites in place of axons. These results suggest that Brn-3b regulates the activity of genes whose products play essential roles in the formation of retinal ganglion cell axons.
Gan
L
L
Department of Biochemistry and Molecular Biology, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas, 77030, USA. lgan@mdanderson.org
Wang
S W
SW
Huang
Z
Z
Klein
W H
WH
D000469:Alkaline Phosphatase / Q000235:genetics; D000483:Alleles; D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D002465:Cell Movement; D002470:Cell Survival; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D005314:Embryonic and Fetal Development; D018507:Gene Expression Regulation, Developmental; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D012160:Retina / Q000196:embryology; D012165:Retinal Ganglion Cells / Q000166:cytology* / Q000502:physiology*; D050818:Transcription Factor Brn-3; D050820:Transcription Factor Brn-3B; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D001616:beta-Galactosidase / Q000235:genetics
D004268:DNA-Binding Proteins; C494190:POU4F2 protein, human; D050818:Transcription Factor Brn-3; D050820:Transcription Factor Brn-3B; D014157:Transcription Factors; D000469:Alkaline Phosphatase; D001616:beta-Galactosidase