title: Neutralization of nerve growth factor impairs proliferation and differentiation of adult neural progenitors in the subventricular zone.
abstract: Adult neurogenesis is a multistep process regulated by several extrinsic factors, including neurotrophins. Among them, little is known about the role of nerve growth factor (NGF) in the neurogenic niches of the mouse. Here we analyzed the biology of adult neural stem cells (NSCs) from the subventricular zone (SVZ) of AD11 anti-NGF transgenic mice, in which the expression of the recombinant antibody aD11 leads to a chronic postnatal neutralization of endogenous NGF. We showed that AD11-NSCs proliferate 10-fold less, with respect to their control counterparts, and display a significant impairment in their ability to differentiate into β-tubulin positive neurons. We found a considerable reduction in the number of SVZ progenitors and neuroblasts also in vivo, which correlates with a lower number of newborn neurons in the olfactory bulbs of AD11 mice and a severe deficit in the ability of these mice to discriminate between different odors. We also demonstrated that, in AD11 mice, the morphology of both SVZ-resident and neurosphere-derived astrocytes is significantly altered. We were able to reproduce the AD11 phenotype in vitro, by acutely treating wild type NSCs with the anti-NGF antibody, further demonstrating that both the proliferation and the differentiation defects are due to the NGF deprivation. Consistently, the proliferative impairment of AD11 progenitors, as well as the atrophic morphology of AD11 astrocytes, can be partly rescued in vitro and in vivo by exogenous NGF addition. Altogether, our results demonstrate a causal link between NGF signaling and proper proliferation and differentiation of neural stem cells from the SVZ.
authors.affiliation: Institute of Translational Pharmacology, National Research Council, Rome, Italy; European Brain Research Institute (EBRI), Rome, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Scardigli
authors.forename: Paolo
authors.initials: P
authors.lastname: Capelli
authors.forename: Domenico
authors.initials: D
authors.lastname: Vignone
authors.forename: Rossella
authors.initials: R
authors.lastname: Brandi
authors.forename: Marcello
authors.initials: M
authors.lastname: Ceci
authors.forename: Federico
authors.initials: F
authors.lastname: La Regina
authors.forename: Eleonora
authors.initials: E
authors.lastname: Piras
authors.forename: Simona
authors.initials: S
authors.lastname: Cintoli
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Berardi
authors.forename: Simona
authors.initials: S
authors.lastname: Capsoni
authors.forename: Antonino
authors.initials: A
authors.lastname: Cattaneo
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D002478:Cells, Cultured; D020547:Lateral Ventricles / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D020932:Nerve Growth Factor / Q000378:metabolism*; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism*; D055495:Neurogenesis / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D020932:Nerve Growth Factor
keywords: Adult neurogenesis; Differentiation; Nerve growth factor; Neural stem cells; Proliferation; Subventricular zone