WAPL functions as a rheostat of Protocadherin isoform diversity that controls neural wiring.

Neural type-specific expression of clustered Protocadherin (Pcdh) proteins is essential for the establishment of connectivity patterns during brain development. In mammals, deterministic expression of the same Pcdh isoform promotes minimal overlap of tiled projections of serotonergic neuron axons throughout the brain, while stochastic expression of Pcdh genes allows for convergence of tightly packed, overlapping olfactory sensory neuron axons into targeted structures. How can the same gene locus generate opposite transcriptional programs that orchestrate distinct spatial arrangements of axonal patterns? Here, we reveal that cell type-specific Pcdh expression and axonal behavior depend on the activity of cohesin and its unloader, WAPL (wings apart-like protein homolog). While cohesin erases genomic-distance biases in Pcdh choice, WAPL functions as a rheostat of cohesin processivity that determines Pcdh isoform diversity.

Whole brain imaging reveals distinct spatial patterns of amyloid beta deposition in three mouse models of Alzheimer's disease.

A variety of Alzheimer's disease (AD) mouse models overexpress mutant forms of human amyloid precursor protein (APP), producing high levels of amyloid ß (Aß) and forming plaques. However, the degree to which these models mimic spatiotemporal patterns of Aß deposition in brains of AD patients is unknown. Here, we mapped the spatial distribution of Aß plaques across age in three APP-overexpression mouse lines (APP/PS1, Tg2576, and hAPP-J20) using in vivo labeling with methoxy-X04, high throughput whole brain imaging, and an automated informatics pipeline. Images were acquired with high resolution serial two-photon tomography and labeled plaques were detected using custom-built segmentation algorithms. Image series were registered to the Allen Mouse Brain Common Coordinate Framework, a 3D reference atlas, enabling automated brain-wide quantification of plaque density, number, and location. In both APP/PS1 and Tg2576 mice, plaques were identified first in isocortex, followed by olfactory, hippocampal, and cortical subplate areas. In hAPP-J20 mice, plaque density was highest in hippocampal areas, followed by isocortex, with little to no involvement of olfactory or cortical subplate areas. Within the major brain divisions, distinct regions were identified with high (or low) plaque accumulation; for example, the lateral visual area within the isocortex of APP/PS1 mice had relatively higher plaque density compared with other cortical areas, while in hAPP-J20 mice, plaques were densest in the ventral retrosplenial cortex. In summary, we show how whole brain imaging of amyloid pathology in mice reveals the extent to which a given model recapitulates the regional Aß deposition patterns described in AD.

Adaptations to skeletal muscle with endurance exercise training in the acutely fed versus overnight-fasted state.

Minimising carbohydrate (CHO) status in the peri-training period may accelerate the training adaptations normally observed. The aim of this study was to compare adaptations to endurance training undertaken in the acutely CHO fed and overnight-fasted states. Eight female and six male untrained, healthy participants: aged 26.6+/-5.8 years (mean+/-SD); height 174.7+/-7.6 cm; weight 75.3+/-11.4 kg; VO(2max) 3.48+/-0.67 l/min; were randomly divided into two training groups and undertook four weeks of five days per week endurance cycle ergometer training in either the overnight-fasted (FAST) or acutely fed (FED) state. FAST training had no effect on RER or plasma glucose, lactate and FFA concentrations during subsequent submaximal exercise. Training-induced changes in Vastus lateralis citrate synthase (CS) and 3-hydroxy-CoA dehydrogenase (HAD) activities were not different between training groups (P=0.655 and 0.549, respectively), but when the effect of gender was considered, men responded better to FAST and women responded better to FED. The FAST group showed a significantly greater training-induced increase in VO(2max) and resting muscle glycogen concentration than FED (P=0.014 and P=0.047 respectively), but there was no gender interaction. In conclusion, these results suggest that (a) meal ingestion prior to daily exercise can modify some of the exercise training-induced adaptations normally seen with endurance training compared to when daily exercise is undertaken in the overnight-fasted state; and (b) the extent of these adaptations in skeletal muscle differ slightly between men and women.

C-type natriuretic peptide forms in the ovine fetal and maternal circulations: evidence for independent regulation and reciprocal response to undernutrition.

C-type natriuretic peptide (CNP) has a crucial role in postnatal endochondral bone growth and is rapidly responsive to changes in nutrition. Although CNP is expressed in the placenta, little is known about the regulation and role of CNP in fetal-maternal health. We hypothesized that CNP may be similarly responsive to undernutrition in the growing fetus, in which maternal nutrition is crucial to normal growth and development. We therefore studied maternal and fetal CNP and the aminoterminal (bioinactive) fragment of proCNP (NTproCNP) in 39 chronically catheterized pregnant sheep before and after a 3-d maternal fast from 121 d gestation. Maternal CNP and NTproCNP levels were higher than in the fetus (CNP 12-fold, NTproCNP 1.5-fold, both P < 0.001). The ratio of NTproCNP to CNP was higher in the fetus than the mother (53 +/- 3 vs. 8.7 +/- 0.6, P < 0.001), suggesting enhanced synthesis and/or degradation of CNP in the fetus. As in postnatal lambs, fetal plasma CNP forms fell promptly during maternal fasting. In contrast, maternal levels exhibited reciprocal and contemporaneous increase, which was reversed by refeeding. Uteroplacental production of CNP was suggested by a high venoarterial concentration gradient across the gravid uterus, and a correlation between maternal NTproCNP levels and placental weight (r(2) = 0.26, P = 0.01). These studies provide the first evidence that CNP is regulated independently in the fetus. Reciprocal increases in maternal CNP forms may reflect the response of the uteroplacental unit to substrate deficiency. CNP may have a role in maintaining fetal welfare and provides a possible marker of uteroplacental nutrient supply.

Nutritional programming of adult disease.

Intrauterine and early neonatal life is a period of physiological plasticity, during which environmental influences may produce long-term effects. Both undernutrition and overnutrition during this period have been shown to change disease risk in adulthood. These effects are influenced by the type, timing and duration of inappropriate nutrition and by the previous nutritional environment and may not be reflected in changes in body size. An understanding of the interaction between nutrient imbalance and alteration of gene expression is likely to be the key to optimising future health outcomes.