title: The CSF-1 receptor ligands IL-34 and CSF-1 exhibit distinct developmental brain expression patterns and regulate neural progenitor cell maintenance and maturation.
abstract: The CSF-1 receptor (CSF-1R) regulates CNS microglial development. However, the localization and developmental roles of this receptor and its ligands, IL-34 and CSF-1, in the brain are poorly understood. Here we show that compared to wild type mice, CSF-1R-deficient (Csf1r-/-) mice have smaller brains of greater mass. They further exhibit an expansion of lateral ventricle size, an atrophy of the olfactory bulb and a failure of midline crossing of callosal axons. In brain, IL-34 exhibited a broader regional expression than CSF-1, mostly without overlap. Expression of IL-34, CSF-1 and the CSF-1R were maximal during early postnatal development. However, in contrast to the expression of its ligands, CSF-1R expression was very low in adult brain. Postnatal neocortical expression showed that CSF-1 was expressed in layer VI, whereas IL-34 was expressed in the meninges and layers II-V. The broader expression of IL-34 is consistent with its previously implicated role in microglial development. The differential expression of CSF-1R ligands, with respect to CSF-1R expression, could reflect their CSF-1R-independent signaling. Csf1r-/- mice displayed increased proliferation and apoptosis of neocortical progenitors and reduced differentiation of specific excitatory neuronal subtypes. Indeed, addition of CSF-1 or IL-34 to microglia-free, CSF-1R-expressing dorsal forebrain clonal cultures, suppressed progenitor self-renewal and enhanced neuronal differentiation. Consistent with a neural developmental role for the CSF-1R, ablation of the Csf1r gene in Nestin-positive neural progenitors led to a smaller brain size, an expanded neural progenitor pool and elevated cellular apoptosis in cortical forebrain. Thus our results also indicate novel roles for the CSF-1R in the regulation of corticogenesis.
authors.affiliation: Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, New York, NY 10461, USA.
authors.forename: Sayan
authors.initials: S
authors.lastname: Nandi
authors.forename: Solen
authors.initials: S
authors.lastname: Gokhan
authors.forename: Xu-Ming
authors.initials: XM
authors.lastname: Dai
authors.forename: Suwen
authors.initials: S
authors.lastname: Wei
authors.forename: Grigori
authors.initials: G
authors.lastname: Enikolopov
authors.forename: Haishan
authors.initials: H
authors.lastname: Lin
authors.forename: Mark F
authors.initials: MF
authors.lastname: Mehler
authors.forename: E Richard
authors.initials: ER
authors.lastname: Stanley
mesh_terms: D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D001921:Brain / Q000002:abnormalities / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism*; D002454:Cell Differentiation; D049109:Cell Proliferation; D002470:Cell Survival; D017931:DNA Primers / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D007378:Interleukins / Q000378:metabolism*; D008024:Ligands; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism*; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D017931:DNA Primers; D007378:Interleukins; D008024:Ligands; C552364:interleukin-34, mouse; D016173:Macrophage Colony-Stimulating Factor; D016186:Receptor, Macrophage Colony-Stimulating Factor