title: Altered cerebellar development in nuclear receptor TAK1/ TR4 null mice is associated with deficits in GLAST(+) glia, alterations in social behavior, motor learning, startle reactivity, and microglia.
abstract: Previously, deficiency in the expression of the nuclear orphan receptor TAK1 was found to be associated with delayed cerebellar granule cell migration and Purkinje cell maturation with a permanent deficit in foliation of lobules VI–VII, suggesting a role for TAK1 in cerebellum development. In this study, we confirm that TAK1-deficient (TAK1(−/−)) mice have a smaller cerebellum and exhibit a disruption of lobules VI–VII. We extended these studies and show that at postnatal day 7, TAK1(−/−) mice exhibit a delay in monolayer maturation of dysmorphic calbindin 28K-positive Purkinje cells. The astrocyte-specific glutamate transporter (GLAST) was expressed within Bergmann fibers and internal granule cell layer at significantly lower levels in the cerebellum of TAK1(−/−) mice. At PND21, Golgi-positive Purkinje cells in TAK1(−/−) mice displayed a smaller soma (18%) and shorter distance to first branch point (35%). Neuronal death was not observed in TAK1(−/−) mice at PND21; however, activated microglia were present in the cerebellum, suggestive of earlier cell death. These structural deficits in the cerebellum were not sufficient to alter motor strength, coordination, or activity levels; however, deficits in acoustic startle response, prepulse startle inhibition, and social interactions were observed. Reactions to a novel environment were inhibited in a light/dark chamber, open-field, and home-cage running wheel. TAK1(−/−) mice displayed a plateau in performance on the running wheel, suggesting a deficit in learning to coordinate performance on a motor task. These data indicate that TAK1 is an important transcriptional modulator of cerebellar development and neurodevelopmentally regulated behavior.
authors.affiliation: Laboratory of Respiratory Biology, Cell Biology Section, Division of Intramural Research, National Institute of Environmental Health Sciences National Institutes of Health, Research Triangle Park, Durham, NC 27709, USA.
authors.forename: Yong-Sik
authors.initials: YS
authors.lastname: Kim
authors.forename: G Jean
authors.initials: GJ
authors.lastname: Harry
authors.forename: Hong Soon
authors.initials: HS
authors.lastname: Kang
authors.forename: David
authors.initials: D
authors.lastname: Goulding
authors.forename: Rob N
authors.initials: RN
authors.lastname: Wine
authors.forename: Grace E
authors.initials: GE
authors.lastname: Kissling
authors.forename: Grace
authors.initials: G
authors.lastname: Liao
authors.forename: Anton M
authors.initials: AM
authors.lastname: Jetten
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D002531:Cerebellum / Q000378:metabolism / Q000473:pathology*; D027341:Excitatory Amino Acid Transporter 1 / Q000378:metabolism; D007858:Learning / Q000502:physiology; D020930:MAP Kinase Kinase Kinases / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000502:physiology; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology*; D013216:Reflex, Startle / Q000502:physiology; D012919:Social Behavior; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D027341:Excitatory Amino Acid Transporter 1; D020930:MAP Kinase Kinase Kinases; D000099151:MAP Kinase Kinase Kinase 7; C493393:Slc1a3 protein, mouse
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