title: Thyroid Hormone-Otx2 Signaling Is Required for Embryonic Ventral Midbrain Neural Stem Cells Differentiated into Dopamine Neurons.
abstract: Midbrain dopamine (DA) neurons are essential for maintaining multiple brain functions. These neurons have also been implicated in relation with diverse neurological disorders. However, how these neurons are developed from neuronal stem cells (NSCs) remains largely unknown. In this study, we provide both in vivo and in vitro evidence that the thyroid hormone, an important physiological factor for brain development, promotes DA neuron differentiation from embryonic ventral midbrain (VM) NSCs. We find that thyroid hormone deficiency during development reduces the midbrain DA neuron number, downregulates the expression of tyrosine hydroxylase (TH) and the dopamine transporter (DAT), and impairs the DA neuron-dependent motor behavior. In addition, thyroid hormone treatment during VM NSC differentiation in vitro increases the production of DA neurons and upregulates the expression of TH and DAT. We also found that the thyroid hormone enhances the expression of Otx2, an important determinant of DA neurogenesis, during DA neuron differentiation. Our in vitro gene silencing experiments indicate that Otx2 is required for thyroid hormone-dependent DA neuron differentiation from embryonic VM NSCs. Finally, we revealed both in vivo and in vitro that the thyroid hormone receptor alpha 1 is expressed in embryonic VM NSCs. Furthermore, it participates in the effects of thyroid hormone-induced Otx2 upregulation and DA neuron differentiation. These data demonstrate the role and molecular mechanisms of how the thyroid hormone regulates DA neuron differentiation from embryonic VM NSCs, particularly providing new mechanisms and a potential strategy for generating dopamine neurons from NSCs.
authors: 1 Department of Occupational Health, Third Military Medical University , Chongqing, China .
authors: Chunhai
authors: C
authors: Chen
authors: 1 Department of Occupational Health, Third Military Medical University , Chongqing, China .
authors: Qinglong
authors: Q
authors: Ma
authors: 2 Brain Research Center, Third Military Medical University , Chongqing, China .
authors: Xiaowei
authors: X
authors: Chen
authors: 1 Department of Occupational Health, Third Military Medical University , Chongqing, China .
authors: Min
authors: M
authors: Zhong
authors: 1 Department of Occupational Health, Third Military Medical University , Chongqing, China .
authors: Ping
authors: P
authors: Deng
authors: 1 Department of Occupational Health, Third Military Medical University , Chongqing, China .
authors: Gang
authors: G
authors: Zhu
authors: 1 Department of Occupational Health, Third Military Medical University , Chongqing, China .
authors: Yanwen
authors: Y
authors: Zhang
authors: 1 Department of Occupational Health, Third Military Medical University , Chongqing, China .
authors: Lei
authors: L
authors: Zhang
authors: 2 Brain Research Center, Third Military Medical University , Chongqing, China .
authors: Zhiqi
authors: Z
authors: Yang
authors: 2 Brain Research Center, Third Military Medical University , Chongqing, China .
authors: Kuan
authors: K
authors: Zhang
authors: 3 Department of Neurology, Daping Hospital, Third Military Medical University , Chongqing, China .
authors: Lu
authors: L
authors: Guo
authors: 4 Biomedical Analysis Center, Third Military Medical University , Chongqing, China .
authors: Liting
authors: L
authors: Wang
authors: 1 Department of Occupational Health, Third Military Medical University , Chongqing, China .
authors: Zhengping
authors: Z
authors: Yu
authors: 1 Department of Occupational Health, Third Military Medical University , Chongqing, China .
authors: Zhou
authors: Z
authors: Zhou
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D059290:Dopaminergic Neurons / Q000166:cytology / Q000378:metabolism*; D005260:Female; D008636:Mesencephalon / Q000166:cytology / Q000196:embryology*; D051379:Mice; D008807:Mice, Inbred BALB C; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism*; D051857:Otx Transcription Factors / Q000378:metabolism*; D013963:Thyroid Hormones / Q000378:metabolism*
chemical_list: D051857:Otx Transcription Factors; C497660:Otx2 protein, mouse; D013963:Thyroid Hormones