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

Ying Sun¹^,5 , Li Jia¹^,5 , Michael T Williams²^,5 , Matt Zamzow¹^,5 , Huimin Ran¹^,5 , Brian Quinn¹^,5 , Bruce J Aronow⁴^,5 , Charles V Vorhees²^,5 , David P Witte³^,6 and Gregory A Grabowski¹^,5

¹Division of Human Genetics, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, MLC 4006, Cincinnati, OH, USA

²Division of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA

³Division of Pediatric Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA

⁴Divisions of Biomedical Informatics and Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA

⁵Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA

⁶Department of Pathology, University of Cincinnati College of Medicine, Cincinnati, OH, USA

author email corresponding author email

BMC Neuroscience 2008, 9:76doi:10.1186/1471-2202-9-76


Published:	1 August 2008

Abstract

Background

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.

Results

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.

Conclusion

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.