Cellular Localization of Gene Expression for Progranulin

Abstract

Granulins, also called epithelins, are 6-kD peptides with growth modulatory effects on a variety of cells. The granulin/epithelin precursor supports tumorigenesis in appropriate cell models and is the only growth factor able to overcome the cell cycle block that occurs in murine fibroblasts after deletion of a functional IGF-1 receptor. However, little is known of the role of granulin/epithelin gene products in vivo. To understand the physiological role of granulins it is essential to know the cell types and conditions in which it is expressed. We examined granulin/epithelin gene expression in adult rodents by in situ hybridization. The granulin/epithelin precursor is constitutively expressed in a number of epithelia, particularly in the skin, GI tract, and reproductive system. Other epithelia express the gene less strongly. Progranulin is expressed in immune cells in vivo and in specific neurons in the brain, including Purkinje cells, pyramidal cells of the hippocampus, and some cerebral cortical neurons. Little expression was detected in muscle cell, connective tissue, or endothelium. Cumulatively, these results define the basal gene expression of a new growth factor system and suggest that the progranulin/epithelin gene is multifunctional, with important constitutive roles in epithelial homeostasis, reproductive, immunological, and neuronal function.

The granulin gene family: from cancer to dementia

“…For adult epithelia it is abundant in regions that are rapidly turning-over, notably in the intestinal deep crypt and epidermal keratinocytes. (42) Other less mitotically active epithelia usually express PGRN at far lower levels. Fibroblasts and endothelial cells, which are normally mitotically quiescent, show corresponding low levels of PGRN.…”

“…Although the relationship between PGRN expression and tissue remodeling is compelling, there are cases where this evidently does not apply, perhaps the most obvious being in the post-mitotic cells of the brain and spinal cord, many of which express PGRN very strongly, (42,51) but are neither proliferating nor migrating. Recent evidence, mostly from the genetics of neurological disease, reveals that PGRN protects neurons from premature death.…”

“…(75) Although PGRN is widely distributed, the pathology due to GRN mutations is highly restricted. PGRN is expressed in many neurons outside the cerebral cortex, (42) but these appear to be far less affected by GRN mutations. Why the cells of the frontal and temporal cortex are so much more sensitive to loss of PGRN than others is not known.…”

Mutations other than null mutations producing a pathogenic loss of progranulin in frontotemporal dementia

“…PGRN is a pluripotent widely expressed growth factor with constitutive roles in development, cell cycle progression, cell motility, wound repair and inflammation. In tumor tissue PGRN was found to be overexpressed [Daniel et al, 2000;]. In the central nervous system PRGN is highly expressed in neurons of the cerebral cortex, particularly in the granule cells of the hippocampus, and in the Purkinje cells of the cerebellum [Daniel et al, 2000].…”

“…In tumor tissue PGRN was found to be overexpressed [Daniel et al, 2000;]. In the central nervous system PRGN is highly expressed in neurons of the cerebral cortex, particularly in the granule cells of the hippocampus, and in the Purkinje cells of the cerebellum [Daniel et al, 2000]. In other neurodegenerative diseases upregulation of PGRN was observed in microglia of Creutzfeldt-Jacob patients and in spinal cord of patients suffering from amyotrophic lateral sclerosis (ALS) [MIM# 105400] [Baker and Manuelidis, 2003;Malaspina et al, 2001].…”