Zic3 enables bimodal regulation of tyrosine hydroxylase expression in dopaminergic neurons of olfactory bulb and midbrain

Abstract

Dopaminergic (DA) neurons in the Olfactory bulb (OB) are involved in odor detection and discrimination. Transcription factor (TF) regulatory network responsible for their fate specification remains poorly understood and the spatial regulation of DA neurons remains elusive. In this study, mice exposed to odor stimulant exhibited specific upregulation of Zinc finger transcription factor of Cerebellum (ZIC) 3 along with Tyrosine Hydroxylase (TH). Stringent co-expression analysis showed ZIC3 and TH dual positive neurons in OB. Genetic manipulation showed ZIC3 to be both essential and sufficient to drive TH expression and essential for odor perception. ZIC3 interacts with ER81 and binds to region encompassing ER81 binding site in DA neurons and is indispensable for TH expression. In midbrain (MB), in the absence of ER81, ZIC3 switches its molecular partner and binds to Pitx3 promoter-a DA fate determinant. Under ectopic expression of ER81 in MB DA neurons, propensity of ZIC3 binding to Pitx3 promoter is compromised and its occupancy on Th promoter encompassing ER81 binding site is established, finally culminating in desired TH expression. Together, these findings reveal a unique ZIC3 mediated bimodal regulation of TH in OB and MB to ultimately facilitate DAergic fate.