Axotomy-induced early down-regulation of POU-IV class transcription factors Brn-3a and Brn-3b in retinal ganglion cells.
It has been proposed that neurons being exposed to proapoptotic stimuli undergo dedifferentiation, a process that can either allow for regeneration and axon regrowth or, if remaining incomplete, can force the cell to activate apoptotic pathways. A pivotal step in the differentiation program from neuronal precursor cells to differentiated, postmitotic neurons is their exit from the cell cycle. The POU domain transcription factors Brn-3b and Brn-3a, which are expressed in retinal ganglion cells (RGCs) directly after the exit of RGC precursors from the cell cycle, can be employed as RGC-specific differentiation markers to study potential dedifferentiation of RGCs after axotomy. Here, we examined mRNAand protein expression of Brn-3a and -3b in rat RGCs following axonal lesion. We observed a rapid down-regulation of Brn-3a and -3b protein expression in axotomized RGCs, clearly preceding apoptosis of RGCs. Using real-time PCR, we show that regulation of Brn-3 expression occurred at the transcriptional level. The small subset of RGCs regenerating into a peripheral nerve graft did not (re-)express Brn-3a or -b. In conclusion, we found further evidence supporting the hypothesis of a dedifferentiation process in severed mature neurons. As Brn-3b expression has been shown to be a prerequisite for developmental survival of most RGCs and Brn-3a activates transcription of anti-apoptotic genes, down-regulation of Brn-3 transcription factors might be causally involved in the secondary death of adult RGCs following axotomy.
Weishaupt
Jochen H
JH
Department of Neurology, University of Göttingen, Göttingen, Germany.
Klöcker
Nikolaj
N
Bähr
Mathias
M
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D019771:Axotomy; D002467:Cell Nucleus / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics*; D005786:Gene Expression Regulation; D008297:Male; D009416:Nerve Regeneration / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012165:Retinal Ganglion Cells / Q000166:cytology / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050818:Transcription Factor Brn-3; D050820:Transcription Factor Brn-3B; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic
D004268:DNA-Binding Proteins; D050818:Transcription Factor Brn-3; D050820:Transcription Factor Brn-3B; D014157:Transcription Factors