POU domain factor Brn-3a controls the differentiation and survival of trigeminal neurons by regulating Trk receptor expression.
Mice lacking the POU domain-containing transcription factor Brn-3a have several neuronal deficits. In the present paper, we show that Brn-3a plays two distinct roles during development of the trigeminal ganglion. In this ganglion, neurons expressing the neurotrophin receptors, TrkB and TrkC, are born between E9.5 and E11.5. In the absence of Brn-3a, very few neurons ever express TrkC, but TrkB-expressing neurons are present at E12.5 in elevated numbers, suggesting that Brn-3a may be a constituent of a regulatory circuit determining which Trk receptor is expressed by these early-born neurons. Most neurons expressing the neurotrophin receptor TrkA are generated between E11.5 and E13.5 in this ganglion and their initial generation is not prevented by absence of Brn-3a. However, after E12. 5, absence of Brn-3a results in a progressive loss in neuronal TrkA and TrkB expression, which leads to a massive wave of apoptosis that peaks at E15.5. Despite complete absence of the Trk receptors at E17. 5 and P0, approximately 30% of the normal complement of neurons survive to birth in Brn-3a mutants. Approximately 70% of these express the GDNF receptor subunit, c-ret; many can be sustained by GDNF, but not by NGF in culture. Thus, the vast majority of surviving neurons are probably sustained in vivo by trophic factor(s) whose receptors are not regulated by Brn-3a. In conclusion, our data indicate the specific functions of Brn-3a in controlling the survival and differentiation of trigeminal neurons by regulating expression of each of the three Trk receptors.
Huang
E J
EJ
Program in Neuroscience, Department of Physiology, and Howard Hughes Medical Institute, University of California, San Francisco, CA 94143-0723. USA.
Zang
K
K
Schmidt
A
A
Saulys
A
A
Xiang
M
M
Reichardt
L F
LF
D000818:Animals; D017209:Apoptosis; D002452:Cell Count; D002454:Cell Differentiation; D002470:Cell Survival; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism*; D029721:Drosophila Proteins; D018507:Gene Expression Regulation, Developmental; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000235:genetics; D009474:Neurons / Q000378:metabolism; D010320:Parvalbumins / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D020801:Receptor, Ciliary Neurotrophic Factor; D020800:Receptor, Nerve Growth Factor; D020917:Receptor, trkA / Q000235:genetics; D020812:Receptor, trkC; D017475:Receptors, Nerve Growth Factor / Q000235:genetics*; D050818:Transcription Factor Brn-3; D050819:Transcription Factor Brn-3A; D014157:Transcription Factors / Q000378:metabolism*; D012668:Trigeminal Ganglion / Q000196:embryology*
D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; C495040:Gdnf protein, mouse; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D010320:Parvalbumins; C494189:Pou4f1 protein, mouse; D011518:Proto-Oncogene Proteins; D020801:Receptor, Ciliary Neurotrophic Factor; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor; D050818:Transcription Factor Brn-3; D050819:Transcription Factor Brn-3A; D014157:Transcription Factors; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; D020917:Receptor, trkA; D020812:Receptor, trkC; C416649:Ret protein, Drosophila; C494999:Ret protein, mouse