title: Developmental Vitamin D (DVD) Deficiency Reduces Nurr1 and TH Expression in Post-mitotic Dopamine Neurons in Rat Mesencephalon.
abstract: Developmental vitamin D (DVD) deficiency has been proposed as an important risk factor for schizophrenia. Our previous study using Sprague Dawley rats found that DVD deficiency disrupted the ontogeny of mesencephalic dopamine neurons by decreasing the mRNA level of a crucial differentiation factor of dopamine cells, the nuclear receptor related 1 protein (Nurr1). However, it remains unknown whether this reflects a reduction in dopamine cell number or in Nurr1 expression. It is also unclear if any particular subset of developing dopamine neurons in the mesencephalon is selectively affected. In this study, we employed state-of-the-art spinning disk confocal microscopy optimized for the imaging of tissue sections and 3D segmentation to assess post-mitotic dopamine cells on a single-cell basis in the rat mesencephalon at embryonic day 15. Our results showed that DVD deficiency did not alter the number, morphology, or positioning of post-mitotic dopamine cells. However, the ratio of Nurr1+TH+ cells in the substantia nigra pars compacta (SNc) compared with the ventral tegmental area (VTA) was increased in DVD-deficient embryos. In addition, the expression of Nurr1 in immature dopamine cells and mature dopamine neurons in the VTA was decreased in DVD-deficient group. Tyrosine hydroxylase was selectively reduced in SNc of DVD-deficient mesencephalon. We conclude that DVD deficiency induced early alterations in mesencephalic dopamine development may in part explain the abnormal dopamine-related behaviors found in this model. Our findings may have broader implications for how certain environmental risk factors for schizophrenia may shape the ontogeny of dopaminergic systems and by inference increase the risk of schizophrenia.
authors.affiliation: Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
authors.forename: Wei
authors.initials: W
authors.lastname: Luan
authors.affiliation: Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
authors.forename: Luke Alexander
authors.initials: LA
authors.lastname: Hammond
authors.affiliation: Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
authors.forename: Edmund
authors.initials: E
authors.lastname: Cotter
authors.affiliation: Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.|The Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD, Australia.
authors.forename: Geoffrey William
authors.initials: GW
authors.lastname: Osborne
authors.affiliation: Queensland Centre for Mental Health Research, Brisbane, QLD, Australia.
authors.forename: Suzanne Adele
authors.initials: SA
authors.lastname: Alexander
authors.affiliation: Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
authors.forename: Virginia
authors.initials: V
authors.lastname: Nink
authors.affiliation: Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Cui
authors.affiliation: Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia. d.eyles@uq.edu.au.|Queensland Centre for Mental Health Research, Brisbane, QLD, Australia. d.eyles@uq.edu.au.
authors.forename: Darryl Walter
authors.initials: DW
authors.lastname: Eyles
mesh_terms: D000818:Animals; D059290:Dopaminergic Neurons / Q000378:metabolism* / Q000473:pathology; D015870:Gene Expression; D008636:Mesencephalon / Q000378:metabolism* / Q000473:pathology; D008938:Mitosis / Q000502:physiology*; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D014446:Tyrosine 3-Monooxygenase / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D014808:Vitamin D Deficiency / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: C539884:Nr4a2 protein, rat; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D014446:Tyrosine 3-Monooxygenase
keywords: Dopamine; Mesencephalon; Nurr1; Schizophrenia; Tyrosine hydroxylase; Vitamin D