TrkB receptor signaling regulates developmental death dynamics, but not final number, of retinal ganglion cells.
We investigated the effects of endogenous neurotrophin signaling on the death-survival of immature retinal ganglion cells (RGCs) in vivo. Null mutation of brain-derived neurotrophic factor [(BDNF) alone or in combination with neurotrophin 4 (NT4)] increases the peak rate of developmental RGC death as compared with normal. Null mutation of NT4 alone is ineffective. Null mutation of the full-length trkB (trkBFL) receptor catalytic domain produces a dose-dependent increase in the peak RGC death rate that is negatively correlated with retinal levels of trkBFL protein and phosphorylated (activated) trkBFL. Depletion of target-derived trkB ligands by injection of trkB-Fc fusion protein into the superior colliculus increases the peak rate of RGC death compared with trkA-Fc-treated and normal animals. Adult trkBFL+/- mice have a normal number of RGCs, despite an elevated peak death rate of immature RGCs. Thus, target-derived BDNF modulates the dynamics of developmental RGC death through trkBFL activation, but BDNF/trkB-independent mechanisms determine the final number of RGCs.
Pollock
Graeme S
GS
Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
Robichon
Regine
R
Boyd
Kristina A
KA
Kerkel
Kristi A
KA
Kramer
Melissa
M
Lyles
Johnalyn
J
Ambalavanar
Ranjini
R
Khan
Asema
A
Kaplan
David R
DR
Williams
Robert W
RW
Frost
Douglas O
DO
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D002452:Cell Count; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D006224:Cricetinae; D007141:Immunoglobulin Fc Fragments / Q000235:genetics; D007278:Injections, Spinal; D008024:Ligands; D008647:Mesocricetus; D051379:Mice; D008817:Mice, Mutant Strains; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism; D020813:Receptor, trkB / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism; D012160:Retina / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013477:Superior Colliculi / Q000187:drug effects
D019208:Brain-Derived Neurotrophic Factor; D007141:Immunoglobulin Fc Fragments; D008024:Ligands; D009414:Nerve Growth Factors; D011993:Recombinant Fusion Proteins; D020813:Receptor, trkB; C073922:neurotrophin 4