Caytaxin deficiency disrupts signaling pathways in cerebellar cortex.
The genetically dystonic (dt) rat, an autosomal recessive model of generalized dystonia, harbors an insertional mutation in Atcay. As a result, dt rats are deficient in Atcay transcript and the neuronally-restricted protein caytaxin. Previous electrophysiological and biochemical studies have defined olivocerebellar pathways, particularly the climbing fiber projection to Purkinje cells, as sites of significant functional abnormality in dt rats. In normal rats, Atcay transcript is abundantly expressed in the granular and Purkinje cell layers of cerebellar cortex. To better understand the consequences of caytaxin deficiency in cerebellar cortex, differential gene expression was examined in dt rats and their normal littermates. Data from oligonucleotide microarrays and quantitative real-time reverse transcriptase-PCR (QRT-PCR) identified phosphatidylinositol signaling pathways, calcium homeostasis, and extracellular matrix interactions as domains of cellular dysfunction in dt rats. In dt rats, genes encoding the corticotropin-releasing hormone receptor 1 (CRH-R1, Crhr1) and plasma membrane calcium-dependent ATPase 4 (PMCA4, Atp2b4) showed the greatest up-regulation with QRT-PCR. Immunocytochemical experiments demonstrated that CRH-R1, CRH, and PMCA4 were up-regulated in cerebellar cortex of mutant rats. Along with previous electrophysiological and pharmacological studies, our data indicate that caytaxin plays a critical role in the molecular response of Purkinje cells to climbing fiber input. Caytaxin may also contribute to maturational events in cerebellar cortex.
Xiao
J
J
University of Tennessee Health Science Center, Departments of Neurology and Anatomy and Neurobiology, Memphis, TN 38163, USA.
Gong
S
S
Ledoux
M S
MS
D000818:Animals; D030801:Animals, Genetically Modified; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism; D002540:Cerebral Cortex / Q000502:physiology*; D004195:Disease Models, Animal; D004421:Dystonia / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D007150:Immunohistochemistry / Q000379:methods; D046228:Microarray Analysis / Q000379:methods; D009419:Nerve Tissue Proteins / Q000172:deficiency*; D010716:Phosphatidylinositols / Q000378:metabolism; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D018019:Receptors, Corticotropin-Releasing Hormone / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D015398:Signal Transduction / Q000502:physiology*; D000099052:CRF Receptor, Type 1
D009419:Nerve Tissue Proteins; D010716:Phosphatidylinositols; D012333:RNA, Messenger; D018019:Receptors, Corticotropin-Releasing Hormone; C508764:atcay protein, rat; D000099052:CRF Receptor, Type 1; D053499:Plasma Membrane Calcium-Transporting ATPases; D002118:Calcium