Chromosome 16p13.11 microduplication is a risk factor associated with various neurodevelopmental disorders such as attention-deficit/hyperactivity disorder, intellectual disabilities, developmental delay and autistic spectrum disorder. The underlying molecular mechanism of this genetic variation remained unknown, but its core genetic locus—conserved across mice and humans—contains seven genes. Here, we generated bacterial artificial chromosome-transgenic mice carrying a human 16p13.11 locus, and these mice showed the behavioral hyperactivity phenotype. We identified miR-484 as the responsible gene using a combination of expression and functional analyses. Mature miR-484 was expressed during active cortical neurogenesis, and overexpression of miR-484 decreased proliferation and increased neural progenitor differentiation in vivo. Luciferase screening identified the 3'-untranslated region of protocadherin-19 (Pcdh19) as a target of miR-484. The effect of miR-484 on neurogenesis was rescued by ectopic PCDH19 expression. These results demonstrate that miR-484 promotes neurogenesis by inhibiting PCDH19. Dysregulation of neurogenesis by imbalanced miR-484/PCDH19 expression contributes to the pathogenesis of 16p13.11 microduplication syndrome.

Abstract. To evaluate the efficiency and accuracy of estrous detection using a new pedometry system that can measure the hourly activity of cattle, pedometers were attached to the neck and the hind legs of 15 Holstein heifers. Heifers were reared in pasture for grazing, an open paddock, or in a tie-stall barn (an additional pedometer was attached to a front leg of each of these heifers). The most recent 24 h-total number of steps was compared for each 1 h-interval with the mean value of the preceding days during the reference period (RP). The neck pedometer detected all 10 instances of estrous activity (100%) for the grazing heifers at 1.3 times the thresholds value for a 5-day RP but with only 32% accuracy. The hind leg pedometer, however, obtained 100% efficiency and 83% accuracy at 1.4 times the threshold value for a 7-day RP. The efficiencies and accuracies in detecting 12 instances of estrous activity under the paddock condition were 92 and 65% (neck, 1.3-fold, 7-day RP) and 92 and 100% (hind leg, 1.6-or 1.7-fold, 7-day RP), respectively. Under the tie stall condition, the neck pedometers detected 92% of 23 instances of estrous activity with 34% accuracy (1.2-fold, 3-day RP), and the efficiencies and accuracies of the leg pedometers were 78 and 78% (hind leg, 1.4-fold, 4-or 6-day RP) and 87 and 83% (front leg, 1.4-fold, 7-day RP), respectively. Prediction of ovulation time was more precisely with the leg pedometers than with those under the tie stall conditions. Our preliminary results indicate that this new pedometer system has practical value for estrous detection in heifers under different rearing conditions, which affect the criteria required for detection. Furthermore, they also indicate that a leg pedometer can reliably detect estrus and that a neck pedometer may only be capable of detecting estrus under paddock rearing conditions.

In amyotrophic lateral sclerosis (ALS) spinal motor neurons (SpMN) progressively degenerate while a subset of cranial motor neurons (CrMN) are spared until late stages of the disease. Using a rapid and efficient protocol to differentiate mouse embryonic stem cells (ESC) to SpMNs and CrMNs, we now report that ESC-derived CrMNs accumulate less human (h)SOD1 and insoluble p62 than SpMNs over time. ESC-derived CrMNs have higher proteasome activity to degrade misfolded proteins and are intrinsically more resistant to chemically-induced proteostatic stress than SpMNs. Chemical and genetic activation of the proteasome rescues SpMN sensitivity to proteostatic stress. In agreement, the hSOD1 G93A mouse model reveals that ALS-resistant CrMNs accumulate less insoluble hSOD1 and p62-containing inclusions than SpMNs. Primary-derived ALS-resistant CrMNs are also more resistant than SpMNs to proteostatic stress. Thus, an ESC-based platform has identified a superior capacity to maintain a healthy proteome as a possible mechanism to resist ALS-induced neurodegeneration.