Brn3b/Brn3c double knockout mice reveal an unsuspected role for Brn3c in retinal ganglion cell axon outgrowth.
In mice, Brn3 POU domain transcription factors play essential roles in the differentiation and survival of projection neurons within the retina, inner ear, dorsal root and trigeminal ganglia. During retinal ganglion cell differentiation, Brn3b is expressed first, followed by Brn3a and Brn3c. Targeted deletion of Brn3b, but not Brn3a or Brn3c, leads to a loss of most retinal ganglion cells before birth. However, as a few retinal ganglion cells are still present in Brn3b(-/-) mice, Brn3a and Brn3c may partially compensate for the loss of Brn3b. To examine the role of Brn3c in retinal ganglion cell development, we generated Brn3b/Brn3c double knockout mice and analyzed their retinas and optic chiasms. Retinal ganglion cell axons from double knockout mice were more severely affected than were those from Brn3b-deficient mice, indicating that Brn3c was required for retinal ganglion cell differentiation and could partially compensate for the loss of Brn3b. Moreover, Brn3c had functions in retinal ganglion cell differentiation separate from those of Brn3b. Ipsilateral and misrouted projections at the optic chiasm were overproduced in Brn3b(-/-) mice but missing were entirely in optic chiasms of Brn3b/Brn3c double knockout mice, suggesting that Brn3c controlled ipsilateral axon production. Forced expression of Brn3c in Brn3b(-/-) retinal explants restored neurite outgrowth, demonstrating that Brn3c could promote axon outgrowth in the absence of Brn3b. Our results reveal a complex genetic relationship between Brn3b and Brn3c in regulating the retinal ganglion cell axon outgrowth.
Wang
Steven W
SW
Department of Biochemistry and Molecular Biology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Mu
Xiuqian
X
Bowers
William J
WJ
Kim
Dong-Seob
DS
Plas
Daniel J
DJ
Crair
Michael C
MC
Federoff
Howard J
HJ
Gan
Lin
L
Klein
William H
WH
D000818:Animals; D001369:Axons / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology*; D046508:Culture Techniques; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D018390:Gene Targeting; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D016501:Neurites / Q000502:physiology; D012160:Retina / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000166:cytology / Q000502:physiology*; D050818:Transcription Factor Brn-3; D050819:Transcription Factor Brn-3A; D050820:Transcription Factor Brn-3B; D050821:Transcription Factor Brn-3C; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; C494189:Pou4f1 protein, mouse; D050818:Transcription Factor Brn-3; D050819:Transcription Factor Brn-3A; D050820:Transcription Factor Brn-3B; D050821:Transcription Factor Brn-3C; D014157:Transcription Factors