Expression Pattern and Neurotrophic Role of the c-fmsProto-Oncogene M-CSF Receptor in Rodent Purkinje Cells

Abstract

To investigate whether the c-fms proto-oncogene plays a role in the CNS, we examined its expression in mouse brain. We found that c-fms-positive Purkinje cells first appeared in caudal cerebellum at postnatal day 0 (P0) arranged in a parasagittal manner, and most Purkinje cells gradually became positive by P6. This differential expression was not seen from P7 to adulthood, and the parasagittal pattern until P5 was different from those of L7, zebrins, and the integrin beta1 subunit. No neuronal expression of c-fms was found in the other brain regions examined. In both reeler and weaver mutant mice in the adult stage, all Purkinje cells were positive for c-fms as in the wild-type controls; however, the parasagittal bands of c-fms-positive Purkinje cells were observed even in the adult staggerer mutant. To check the neurotrophic effect of macrophage colony-stimulating factor (M-CSF), we immunostained cerebella derived from osteopetrotic mutant mice, that is, those devoid of active M-CSF. We found that the number of calbindin-positive Purkinje cells in a given cerebellum began to decrease substantially during the initial 4-5 weeks of the postnatal period. In addition, cultured Purkinje cells were dependent on M-CSF for their survival. These data suggest that expression of the c-fms gene is intrinsically programmed in the Purkinje cells and never affected by the afferent synaptic input and that neuronal survival of Purkinje cells is dependent on M-CSF after weaning. Therefore, c-fms is considered to be a new developmental marker for Purkinje cells.

Purkinje cell fate instaggerer mutants: Agenesis versus cell death

“…Other studies have shown that NMDA and GABA receptor subtypes are aberrantly expressed in sg/sg Purkinje cells (Luntz-Leybman et al, 1995;Nakagawa et al, 1996). The expression of calmodulin (Messer et al, 1990), the integrin ␤1 subunit (Murase and Hayashi, 1996), and c-fms (Murase and Hayashi, 1998) are developmentally arrested in staggerer. cfms expression may be particularly important for Purkinje cell survival, since it is the receptor for the proto-oncogene macrophage colony-stimulating factor, a putative trophic factor for Purkinje cells (Murase and Hayashi, 1998).…”

“…The expression of calmodulin (Messer et al, 1990), the integrin ␤1 subunit (Murase and Hayashi, 1996), and c-fms (Murase and Hayashi, 1998) are developmentally arrested in staggerer. cfms expression may be particularly important for Purkinje cell survival, since it is the receptor for the proto-oncogene macrophage colony-stimulating factor, a putative trophic factor for Purkinje cells (Murase and Hayashi, 1998). Only a relatively few sg/sg Purkinje cells in parasagittal bands in the vermis and lateral hemispheres express c-fms in staggerer at P6, whereas all Purkinje cells express c-fms by this age in controls.…”

Targeted disruption of the mouse colony-stimulating factor 1 receptor gene results in osteopetrosis, mononuclear phagocyte deficiency, increased primitive progenitor cell frequencies, and reproductive defects

“…9 The CSF-1R is expressed on primitive multipotent hematopoietic cells, 10,11 mononuclear phagocyte progenitor cells, 12 monoblasts, promonocytes, monocytes, 5,6 tissue macrophages, 6,[13][14][15] osteoclasts, 16 B cells, 17,18 smooth muscle cells, 19 and neurons. 20,21 CSF-1R messenger RNA (mRNA) is expressed in Langerhans cells, 22 in the female reproductive tract, in oocytes and embryonic cells of the inner cell mass and trophectoderm, 23 in decidual cells, [24][25][26] and in cells of the trophoblast. 24,25 The expression of the CSF-1R on primitive hematopoietic cells that are unable to proliferate in vitro in response to CSF-1 alone 10,11 but are able to proliferate and differentiate if stimulated with combinations of CSF-1 and other hematopoietic growth factors 10,11,27 suggests that CSF-1R is involved in the regulation of more primitive hematopoietic cells than those that form macrophage colonies in vitro in response to CSF-1 alone.…”

Microglia Overexpressing the Macrophage Colony-Stimulating Factor Receptor Are Neuroprotective in a Microglial-Hippocampal Organotypic Coculture System

“…This may result in neuronal self-protection through autocrine and paracrine M-CSF signaling. Some, but not all, studies have reported neuronal expression of the M-CSFR that varies depending on age and anatomic region (Murase and Hayashi, 1998;Raivich et al, 1998). Injury induces neuronal M-CSFR expression locally (Wang et al, 1999).…”