title: Glucocorticoid Effects on Cerebellar Development in a Chicken Embryo Model: Exploring Changes in PAX6 and Metalloproteinase-9 After Exposure to Dexamethasone.
abstract: The developing cerebellum is vulnerable to effects of glucocorticoids and cerebellar dysfunction is associated with neurodevelopmental disorders (e.g. autism). Transcription factor PAX6 and matrix metalloproteinase-9 (MMP-9) are critical for normal cerebellar development and are highly expressed in migrating neurones. Alterations in MMP-9 and PAX6 are associated with altered cerebellar development. In the present study, we characterised the growth rate and development of the cortical layers, and further investigated how the levels of PAX6 and MMP-9, as well as glucocorticoid receptor (GR) and proliferating cell nuclear antigen (PCNA), change in the cerebellum during the foetal period [embryonic day (E)12-21] in chicken, which corresponds to the human perinatal period. Dexamethasone (DEX) was administered in ovo at E13 and E16, aiming to investigate how prenatal exposure to glucocorticoids interferes with normal development. DEX reduced foetal and cerebellar weight at E17 in a dose-dependent manner linked to a reduced level of PCNA and, over time, down-regulation of GR. We report that promoter activity of PAX6 and MMP-9 increased as a result of GR-stimulation in vitro. Prenatal DEX increased the protein level of PAX6 in a transient manner. PAX6 is reduced in mature granule neurones, and this occurred earlier in embryos exposed to DEX than in non-exposed controls. DEX exposure also led to a slow-onset down-regulation of MMP-9. Taken together, these findings indicate that excess prenatal glucocorticoid stimulation disturbs normal development of the cerebellum through mechanisms associated with reduced proliferation and accelerated maturation where PAX6 and MMP-9 play important roles.
authors: Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway.
authors: L P E
authors: LP
authors: Austdal
authors: Department of Pathology, Oslo University Hospital - Ullevål, Oslo, Norway.
authors: S
authors: S
authors: Bjørnstad
authors: Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway.
authors: G H
authors: GH
authors: Mathisen
authors: Department of Neurosciences for Children, Oslo University Hospital, University of Oslo, Oslo, Norway.
authors: P K
authors: PK
authors: Aden
authors: Department of Pharmacy, Faculty of Health Sciences, UiT - The Arctic University of Norway, Tromsø, Norway.
authors: I
authors: I
authors: Mikkola
authors: Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway.
authors: R E
authors: RE
authors: Paulsen
authors: Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway.
authors: K E
authors: KE
authors: Rakkestad
mesh_terms: D000818:Animals; D030161:Avian Proteins / Q000378:metabolism; D002531:Cerebellum / Q000187:drug effects* / Q000196:embryology* / Q000378:metabolism; D002642:Chick Embryo; D002645:Chickens; D003907:Dexamethasone / Q000008:administration & dosage / Q000378:metabolism*; D005938:Glucocorticoids / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D009929:Organ Size; D000071841:PAX6 Transcription Factor / Q000378:metabolism*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011965:Receptors, Glucocorticoid / Q000378:metabolism
chemical_list: D030161:Avian Proteins; D005938:Glucocorticoids; D000071841:PAX6 Transcription Factor; D018809:Proliferating Cell Nuclear Antigen; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone; D020780:Matrix Metalloproteinase 9
keywords: MMP-9; PAX6; cerebellum; glucocorticoid; maturation