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.

CSF-1 Receptor Signaling in Myeloid Cells

“…It is also expressed on oocytes and preimplantation embryos, decidual and trophoblastic cells (reviewed in Pollard and Stanley 1996), neural progenitor cells and other neuronal cells (Wang et al 1999a;Nandi et al 2012;Luo et al 2013), renal proximal tubule epithelial cells, and colonic epithelial cells (reviewed in Chitu and Stanley 2014). The broad pattern of expression of CSF-1R is consistent with its pleiotropic actions in embryonic development, adult physiology, innate immunity, inflammation, tissue repair, and in the tumor microenvironment (reviewed in Chitu and Stanley 2014).…”

“…Both in vitro and when expressed in vivo under the control of the CSF-1 promoter, the biological activities of homodimeric glycoprotein interleukin-34 (IL-34) resemble those of the secreted glycoprotein isoform of CSF-1 (Wei et al 2010). Although there are significant differences in their signaling through the CSF-1R (Chihara et al 2010), it is primarily the differential expression of IL-34 and CSF-1 (Wei et al 2010;Greter et al 2012;Nandi et al 2012;Wang et al 2012) that results in their differential spatiotemporal regulation through the CSF-1R in vivo (Wei et al 2010;Nandi et al 2012). The transmembrane and proteoglycan CSF-1 isoforms act locally (Wiktor-Jedrzejczak et al 1991;Sundquist et al 1995;Van Nguyen and Pollard 2002;Dai et al 2004;Nandi et al 2006).…”

“…In contrast, IL-34 is not detectable in the circulation of healthy individuals (Hwang et al 2012;Tian et al 2013) and thus IL-34 actions are likely to be restricted to the local microenvironments in which they are expressed. Through their different spatiotemporal expression, the two ligands play complementary roles in regulating the development, maintenance, and activity of specific macrophage populations, Langerhans cells, neuronal progenitors (Wei et al 2010;Greter et al 2012;Nandi et al 2012;Wang et al 2012), as well as osteoclasts (Dai et al 2002) and Paneth cells (Huynh et al 2009) and the regulation of cells of the female reproductive tract (Wei et al 2010). Because all of the CSF-1 deficiency phenotypes are also shared with CSF-1R-deficient mice (Dai et al 2002), the CSF-1R appears to be the only receptor for CSF-1, whereas IL-34 has recently been shown to act via an additional receptor, receptortype protein tyrosine phosphatase-z (PTP-z) (Nandi et al 2013).…”

Cytokine regulation of stem cells

“…Mice lacking IL-34 displayed reduced Langerhans cells and diminished microglial cells. However, no effect was seen on monocytes, macrophages, and dendritic cells [36]. IL-34 appears to be indispensible for the development of Langerhans cells not only during embryogenesis but also during normal homeostasis in the adult skin [36].…”

“…However, no effect was seen on monocytes, macrophages, and dendritic cells [36]. IL-34 appears to be indispensible for the development of Langerhans cells not only during embryogenesis but also during normal homeostasis in the adult skin [36]. Though, repopulation of Langerhans cells during inflammation appears to be dependent on Csf-1, postinflammation survival of Langerhans cells is IL-34 dependent.…”