Normal Midbrain Dopaminergic Neuron Development and Function in miR-133b Mutant Mice

Abstract

Midbrain dopaminergic (mDA) neurons control movement and emotion, and their degeneration leads to motor and cognitive defects in Parkinson's disease (PD). miR-133b is a conserved microRNA that is thought to regulate mDA neuron differentiation by targeting Pitx3, a transcription factor required for appropriate development of mDA substantia nigra neurons. Moreover, miR-133b has been found to be depleted in the midbrain of PD patients. However, the function of miR-133b in the intact midbrain has not been determined. Here we show that miR-133b null mice have normal numbers of mDA neurons during development and aging. Dopamine levels are unchanged in the striatum, while expression of dopaminergic genes, including Pitx3, is also unaffected. Finally, motor coordination and both spontaneous and psychostimulant-induced locomotion are unaltered in miR-133b null mice, suggesting that miR-133b does not play a significant role in mDA neuron development and maintenance in vivo.

MicroRNAs in neural development: from master regulators to fine-tuners

“…Interestingly, it has been reported that miR-133b levels are decreased in the brains of individuals with Parkinson's disease compared with healthy controls (Kim et al, 2007), suggesting that an interaction between Pitx3 and miR-133b is necessary to maintain a stable population of dopaminergic neurons. In contrast, a separate study using systemic Mir133b KO in mice did not find any defects in dopaminergic neuron development and maintenance in vivo (Heyer et al, 2012), casting some doubt on the physiological relevance of the miR-133b/Pitx3 pathway in dopaminergic neuron differentiation. One possible explanation for these disparate findings is that the systemic loss of miR-133b during development causes compensatory mechanisms to be engaged in the KO mice.…”

Serum microRNA-133b is associated with low ceruloplasmin levels in Parkinson's disease

“…Kim and colleagues revealed that miR-133b was down-regulated in the development of dopaminergic neuron in the midbrain through a feedback loop between miR-133b and pairedlike homeodomain transcription factor 3 (Pitx3) [19]. However, Heyer and colleagues found no significant effect of miR-133b on the number of dopaminergic neurons in the midbrain of mice during development and aging [26]. de Mena and colleagues found no association between PD and genetic variants of miR-133b and Pitx3 [27].…”

Roles of the canonical myomiRs miR-1, -133 and -206 in cell development and disease

“…Together, these findings imply that miR206 is the major regulator of nerve repair and reconnection to muscle following injury. In support, in miR133b null mice Pitx3 levels were normal and impairment of locomotion was not detectable, controversially implying that miR133b has no significant roles in neuron development, neuron maintenance and function in vivo [45] . In contrast, other studies with miR206 null mice show no obvious phenotypic effects, muscles develop normally and mouse physiology appears normal, suggesting that other factors (including miR133b) can replace miR206 during development [46] .…”