Dataset Information

Temporal gene expression profiling reveals CEBPD as a candidate regulator of brain disease in prosaposin deficient mice.

ABSTRACT: Prosaposin encodes, in tandem, four small acidic activator proteins (saposins) with specificities for glycosphingolipid (GSL) hydrolases in lysosomes. Extensive GSL storage occurs in various central nervous system regions in mammalian prosaposin deficiencies.Our hypomorphic prosaposin deficient mouse, PS-NA, exhibited 45% WT levels of brain saposins and showed neuropathology that included neuronal GSL storage and Purkinje cell loss. Impairment of neuronal function was observed as early as 6 wks as demonstrated by the narrow bridges tests. Temporal transcriptome microarray analyses of brain tissues were conducted with mRNA from three prosaposin deficient mouse models: PS-NA, prosaposin null (PS-/-) and a V394L/V394L glucocerebrosidase mutation combined with PS-NA (4L/PS-NA). Gene expression alterations in cerebrum and cerebellum were detectable at birth preceding the neuronal deficits. Differentially expressed genes encompassed a broad spectrum of cellular functions. The number of down-regulated genes was constant, but up-regulated gene numbers increased with age. CCAAT/enhancer-binding protein delta (CEBPD) was the only up-regulated transcription factor in these two brain regions of all three models. Network analyses revealed that CEBPD has functional relationships with genes in transcription, pro-inflammation, cell death, binding, myelin and transport.These results show that: 1) Regionally specific gene expression abnormalities precede the brain histological and neuronal function changes, 2) Temporal gene expression profiles provide insights into the molecular mechanism during the GSL storage disease course, and 3) CEBPD is a candidate regulator of brain disease in prosaposin deficiency to participate in modulating disease acceleration or progression.

SUBMITTER: Sun Y

PROVIDER: S-EPMC2518924 | biostudies-literature | 2008 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Temporal gene expression profiling reveals CEBPD as a candidate regulator of brain disease in prosaposin deficient mice.

Sun Ying Y Jia Li L Williams Michael T MT Zamzow Matt M Ran Huimin H Quinn Brian B Aronow Bruce J BJ Vorhees Charles V CV Witte David P DP Grabowski Gregory A GA

BMC neuroscience 20080801

<h4>Background</h4>Prosaposin encodes, in tandem, four small acidic activator proteins (saposins) with specificities for glycosphingolipid (GSL) hydrolases in lysosomes. Extensive GSL storage occurs in various central nervous system regions in mammalian prosaposin deficiencies.<h4>Results</h4>Our hypomorphic prosaposin deficient mouse, PS-NA, exhibited 45% WT levels of brain saposins and showed neuropathology that included neuronal GSL storage and Purkinje cell loss. Impairment of neuronal funct ...[more]

PMID: 18673548

Similar Datasets

Project description:The expression of prosaposin is temporally and spatially regulated at transcriptional and post-translational levels. Transgenic mice with various 5'-flanking deletions of the prosaposin promoter fused to luciferase (LUC) reporters were used to define its temporal regulatory region. LUC expression in the transgenic mice carrying constructs with 234 bp (234LUC), 310 bp (310LUC) or 2400 bp (2400LUC) of the 5'-flanking region was analysed in the central nervous system and eye throughout development. For 310LUC and 2400LUC, low-level LUC activity was maintained until embryonal day 18 in brain, eye and spinal cord. The peak level of LUC activity was at birth, with return to a plateau (1/3 of peak) throughout adulthood. Deletion of the region that included the retinoic acid-receptor-related orphan receptor (ROR alpha)-binding site and sequence-specific transcription factor (Sp1) cluster sites (44-310 bp) suppressed the peak of activity. By comparison, the peak level for 234LUC was shifted 2 weeks into neonatal life in the brain, but not in the eye, and no peak of activity was observed in the spinal cord. The endogenous prosaposin mRNA in eye, spinal cord and cerebellum had low-level expression before birth and continued to increase into adulthood. In cerebrum, the endogenous mRNA showed similar expression profile to constructs 310LUC, 2400LUC and 234LUC, with the peak expression at 1 week and a decreased level in adult. In the brain of the newborn, 2400LUC was highly expressed in the trigeminal ganglion and brain stem regions when compared with the generalized expression pattern for endogenous prosaposin mRNA. These results suggest that the modifiers (ROR alpha- and Sp1-binding sites) residing within 310 bp of the 5'-flanking region mediate developmental regulation in the central nervous system and eye. Additional regulatory elements outside the 5' region of the 2400 bp promoter fragment appear to be essential for the physiological control of the prosaposin locus.

Dataset Information

Temporal gene expression profiling reveals CEBPD as a candidate regulator of brain disease in prosaposin deficient mice.

Publications

Temporal gene expression profiling reveals CEBPD as a candidate regulator of brain disease in prosaposin deficient mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets