MicroRNAs (miRNAs) are small noncoding RNAs that may work to repress

MicroRNAs (miRNAs) are small noncoding RNAs that may work to repress focus on mRNAs by suppressing translation and/or reducing mRNA stability. animal. The lack of profound cell death contrasts with other mouse models in which Dicer has been ablated. These studies highlight the complicated nature of Dicer ablation in the brain and provide a useful mouse model for studying dopaminoceptive neuron function. roles of Dicer and miRNAs in the brain. One recent study determined that loss of Dicer in postmitotic Purkinje neurons results in profound neurodegeneration that becomes readily apparent between 13 and 17 weeks of age (8). Thus, Dicer loss in Purkinje neurons leads to cell death similar to that found in other published Dicer loss studies. In these studies, we created a conditional mouse model to ablate Dicer in dopaminoceptive neurons by using a dopamine receptor-1 free base kinase activity assay (DR-1) Cre. Drd1a (DR-1) is broadly expressed in the basal ganglia of the postnatal brain but is most highly expressed in the GABAergic, medium spiny neurons of the striatum (9). These neurons are involved in mediating numerous functions including initiation of movement, cognition, and feeding behavior. Dysfunction of dopaminoceptive neurons has been implicated in several human disorders such as Parkinson’s disease, drug addiction, schizophrenia, obsessiveCcompulsive disorder, and Rett syndrome (10C13). To date, there is not much known about what roles that Dicer and small RNAs may have in the pathology of human neurological disorders. A recent study demonstrated that disruption of Dicer with a dopamine transporter (DAT) Cre in postmitotic midbrain dopaminergic neurons leads to the loss of 90% of the cells in the substantia nigra and ventral tegmental area by 8 weeks of age, the class of neurons affected in Parkinson’s disease (7). In our study, we examined a class of neurons that receive inputs from DAT neurons, and we found that removal of Dicer in these cells leads to distinct phenotypes from those seen in the DAT Cre mice or any other mouse model in which Dicer has been ablated. Despite the observed phenotypes, Dicer knockout dopaminoceptive neurons survive over the life of the animal, raising the possibility that these lines could be used to study human neurological disorders. Results Loss of Dicer in DR-1 Neurons Leads to Behavioral Defects and Decreased Lifespan. To investigate the role of Dicer in postmitotic DR-1 neurons, we crossed mice conditional for Dicer ((Fig. 1animals appear to be normal at birth, exhibiting normal weights and weaning behaviors as compared with controls (data not shown). Rabbit Polyclonal to NPY5R At 6 weeks of free base kinase activity assay age, the animals begin to undergo wasting and continue to lose weight until their loss of life, which happens between 10 and 12 weeks of age. Females exhibit a median lifespan shorter than males (median lifespan females: 69 days, = 22; males: 78 days, = 21), which may be caused by their smaller size and body mass (for weights: = 13 for each female genotype and = 14 for each male genotype; Student’s test was performed and 0.0001 for both males and females) (Fig. 1 and cre mice. (conditional targeting construct. (animals. animals were utilized as controls for everyone experiments. (pets in comparison with handles. Females possess a median life expectancy of 69 times (= 22) and men have got a median life expectancy of 78 times (= 21). (pets exhibit throwing away and lack of body mass in comparison with handles. ***, 0.0001 for females (= 13) and men (= 14), Student’s check. SEM is certainly shown. (pets reveals unusual gait. (pets in comparison with handles (= 8; **, = 0.0004, Student’s test). SEM is certainly proven. Because DR-1-expressing neurons are key afferents inside the basal ganglia, which play a central function in the initiation of motion, we searched for to determine whether these pets displayed flaws in motion. At four weeks old, allanimals create a solid entrance and hind limb clasping phenotype, as dependant on a tail-suspension assay (Fig. 1animals display free base kinase activity assay deep gait abnormalities, acquiring brief, wobbly strides, as uncovered by footprint evaluation.