title: Temporal gene expression profiling reveals CEBPD as a candidate regulator of brain disease in prosaposin deficient mice.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, MLC 4006, Cincinnati, OH, USA. ying.sun@cchmc.org
authors.forename: Ying
authors.initials: Y
authors.lastname: Sun
authors.forename: Li
authors.initials: L
authors.lastname: Jia
authors.forename: Michael T
authors.initials: MT
authors.lastname: Williams
authors.forename: Matt
authors.initials: M
authors.lastname: Zamzow
authors.forename: Huimin
authors.initials: H
authors.lastname: Ran
authors.forename: Brian
authors.initials: B
authors.lastname: Quinn
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Aronow
authors.forename: Charles V
authors.initials: CV
authors.lastname: Vorhees
authors.forename: David P
authors.initials: DP
authors.lastname: Witte
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Grabowski
mesh_terms: D000367:Age Factors; D000818:Animals; D001927:Brain Diseases / Q000235:genetics* / Q000503:physiopathology; D051743:CCAAT-Enhancer-Binding Protein-delta / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D002531:Cerebellum / Q000473:pathology / Q000503:physiopathology; D054022:Cerebrum / Q000473:pathology / Q000503:physiopathology; D016000:Cluster Analysis; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics; D020869:Gene Expression Profiling; D005809:Genes, Regulator; D005962:Glucosylceramidase / Q000172:deficiency / Q000235:genetics; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D046228:Microarray Analysis / Q000379:methods / Q000706:statistics & numerical data; D009043:Motor Activity / Q000502:physiology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D011689:Purkinje Cells / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D049231:Saposins / Q000172:deficiency* / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics
chemical_list: C497253:Cebpd protein, mouse; C483344:Psap protein, mouse; D012333:RNA, Messenger; D049231:Saposins; D051743:CCAAT-Enhancer-Binding Protein-delta; D005962:Glucosylceramidase