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Glucocorticoid Effects on Cerebellar Development in a Chicken Embryo Model: Exploring Changes in PAX 6 and Metalloproteinase ‐9 After Exposure to Dexamethasone
Author(s) -
Austdal L. P. E.,
Bjørnstad S.,
Mathisen G. H.,
Aden P. K.,
Mikkola I.,
Paulsen R. E.,
Rakkestad K. E.
Publication year - 2016
Publication title -
journal of neuroendocrinology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.062
H-Index - 116
eISSN - 1365-2826
pISSN - 0953-8194
DOI - 10.1111/jne.12438
Subject(s) - medicine , endocrinology , cerebellum , glucocorticoid , glucocorticoid receptor , biology , dexamethasone , stimulation , proliferating cell nuclear antigen , embryo , immunohistochemistry , microbiology and biotechnology
The developing cerebellum is vulnerable to effects of glucocorticoids and cerebellar dysfunction is associated with neurodevelopmental disorders (e.g. autism). Transcription factor PAX 6 and matrix metalloproteinase‐9 ( MMP ‐9) are critical for normal cerebellar development and are highly expressed in migrating neurones. Alterations in MMP ‐9 and PAX 6 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 PAX 6 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 PAX 6 and MMP ‐9 increased as a result of GR ‐stimulation in vitro . Prenatal DEX increased the protein level of PAX 6 in a transient manner. PAX 6 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 PAX 6 and MMP ‐9 play important roles.