Journal Article

The essential role of transcription factor Pitx3 in preventing mesodiencephalic dopaminergic neurodegeneration and maintaining neuronal subtype identities during aging

Wang, Yuanyuan, Wang, Ying, Chen, Xi, Li, Song, Cai, Huaibin, Le, Weidong

2021

Overview

Pituitary homeobox 3 ( Pitx3 ) is required for the terminal differentiation of nigrostriatal dopaminergic neurons during neuronal development. However, whether Pitx3 contributes to the normal physiological function and cell-type identity of adult neurons remains unknown. To explore the role of Pitx3 in maintaining mature neurons, we selectively deleted Pitx3 in the mesodiencephalic dopaminergic (mdDA) neurons of Pitx3 fl/fl/ DAT CreERT2 bigenic mice using a tamoxifen inducible Cre ERT2 / loxp gene-targeting system. Pitx3 fl/fl/ DAT CreERT2 mice developed age-dependent progressive motor deficits, concomitant with a rapid reduction of striatal dopamine (DA) content and a profound loss of mdDA neurons in the substantia nigra pars compacta (SNc) but not in the adjacent ventral tegmental area (VTA), recapitulating the canonical neuropathological features of Parkinson’s disease (PD). Mechanistic studies showed that Pitx3 -deficiency significantly increased the number of cleaved caspase-3 + cells in SNc, which likely underwent neurodegeneration. Meanwhile, the vulnerability of SNc mdDA neurons was increased in Pitx3 fl/fl/ DAT CreERT2 mice, as indicated by an early decline in glial cell line-derived neurotrophic factor (GDNF) and aldehyde dehydrogenase 1a1 (Aldh1a1) levels. Noticeably, somatic accumulation of α-synuclein (α-syn) was also significantly increased in the Pitx3 -deficient neurons. Together, our data demonstrate that the loss of Pitx3 in fully differentiated mdDA neurons results in progressive neurodegeneration, indicating the importance of the Pitx3 gene in adult neuronal survival. Our findings also suggest that distinct Pitx3-dependent pathways exist in SNc and VTA mdDA neurons, correlating with the differential vulnerability of SNc and VTA mdDA neurons in the absence of Pitx3 .

• Publisher: Nature Publishing Group UK,Springer Nature B.V,Nature Publishing Group
• Subject: 13/1 / 13/2 / 14/19 / 14/32 / 14/63 / 38/1 / 631/378 / 64/60 / 692/699/375 / 82/1 / 82/51 / Aging / Aging - genetics / Aldehyde dehydrogenase / Animals / Antibodies / Biochemistry / Biomedical and Life Sciences / Caspase-3 / Cell Biology / Cell Culture / Cell Differentiation / Dopamine receptors / Dopaminergic Neurons - metabolism / Glial cell line-derived neurotrophic factor / Homeobox / Homeodomain Proteins - metabolism / Immunology / Life Sciences / LoxP gene / Mice / Movement disorders / Neostriatum / Neurodegeneration / Neurodegenerative diseases / Neurogenesis - genetics / Neuronal-glial interactions / Parkinson's disease / Pituitary / Pitx3 gene / Substantia nigra / Synuclein / Transcription Factors - metabolism / Ventral tegmentum