TY - JOUR
T1 - The CSF-1 receptor ligands IL-34 and CSF-1 exhibit distinct developmental brain expression patterns and regulate neural progenitor cell maintenance and maturation
AU - Nandi, Sayan
AU - Gokhan, Solen
AU - Dai, Xu Ming
AU - Wei, Suwen
AU - Enikolopov, Grigori
AU - Lin, Haishan
AU - Mehler, Mark F.
AU - Richard Stanley, E.
N1 - Funding Information:
We thank Halley Ketchum and Xiao-Hua Zong for technical assistance and Dr. J.W. Pollard for the Csf 1 r fl/fl mice. We also thank the Einstein histopathology, FACS and analytical imaging facilities. This work was supported by: NIH grants CA32551 and CA26504 (to ERS) and NS071571 and HD071593 (to MFM), NIMH and NYSTEM (to GE) and the Albert Einstein College of Medicine Cancer Center grant 5P30-CA13330 .
PY - 2012/7/15
Y1 - 2012/7/15
N2 - 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 (. Csf1. r-/-) 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. . Csf1. r-/. - 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 . Csf1. r 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.
AB - 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 (. Csf1. r-/-) 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. . Csf1. r-/. - 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 . Csf1. r 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.
KW - CSF-1
KW - Cerebral cortex
KW - IL-34
KW - Nestin
KW - Neural stem cells
KW - Neurogenesis
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U2 - 10.1016/j.ydbio.2012.03.026
DO - 10.1016/j.ydbio.2012.03.026
M3 - Article
C2 - 22542597
AN - SCOPUS:84862122306
SN - 0012-1606
VL - 367
SP - 100
EP - 113
JO - Developmental Biology
JF - Developmental Biology
IS - 2
ER -