Targeting novel integrative nuclear FGFR1 signaling by nanoparticle-mediated gene transfer stimulates neurogenesis in the adult brain.
Neurogenesis, the process of differentiation of neuronal stem/progenitor cells (NS/PC) into mature neurons, holds the key to the treatment of various neurodegenerative disorders, which are a major health issue for the world's aging population. We report that targeting the novel integrative nuclear FGF Receptor 1 signaling (INFS) pathway enhances the latent potential of NS/PCs to undergo neuronal differentiation, thus promoting neurogenesis in the adult brain. Employing organically modified silica (ORMOSIL)-DNA nanoplexes to efficiently transfect recombinant nuclear forms of FGFR1 and its FGF-2 ligand into the brain subventricular zone, we find that INFS stimulates the NS/PC to withdraw from the cell cycle, differentiate into doublecortin expressing migratory neuroblasts and neurons that migrate to the olfactory bulb, subcortical brain regions and in the brain cortex. Thus, nanoparticle-mediated non-viral gene transfer may be used to induce selective differentiation of NS/PCs, providing a potentially significant impact on the treatment of a broad range of neurological disorders.
Stachowiak
Ewa K
EK
Molecular and Structural Neurobiology and Gene Therapy Program, Department of Pathology and Anatomical Sciences, State University of New York, Buffalo, NY 14214, USA.
Roy
Indrajit
I
Lee
Yu-Wei
YW
Capacchietti
Mariolina
M
Aletta
John M
JM
Prasad
Paras N
PN
Stachowiak
Michal K
MK
D000818:Animals; D001921:Brain / Q000166:cytology* / Q000502:physiology*; D002478:Cells, Cultured; D004337:Drug Carriers / Q000737:chemistry; D005260:Female; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000737:chemistry*; D055495:Neurogenesis / Q000502:physiology*; D009474:Neurons / Q000166:cytology* / Q000502:physiology*; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection / Q000379:methods*
D004337:Drug Carriers; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1