SHR and SCR coordinate root patterning and growth early in the cell cycle.

Precise control of cell division is essential for proper patterning and growth during the development of multicellular organisms. Coordination of formative divisions that generate new tissue patterns with proliferative divisions that promote growth is poorly understood. SHORTROOT (SHR) and SCARECROW (SCR) are transcription factors that are required for formative divisions in the stem cell niche of Arabidopsis roots1,2. Here we show that levels of SHR and SCR early in the cell cycle determine the orientation of the division plane, resulting in either formative or proliferative cell division. We used 4D quantitative, long-term and frequent (every 15 min for up to 48 h) light sheet and confocal microscopy to probe the dynamics of SHR and SCR in tandem within single cells of living roots. Directly controlling their dynamics with an SHR induction system enabled us to challenge an existing bistable model3 of the SHR-SCR gene-regulatory network and to identify key features that are essential for rescue of formative divisions in shr mutants. SHR and SCR kinetics do not align with the expected behaviour of a bistable system, and only low transient levels, present early in the cell cycle, are required for formative divisions. These results reveal an uncharacterized mechanism by which developmental regulators directly coordinate patterning and growth.

Oral zinc reduces amyloid burden in Tg2576 mice.

The aggregation of amyloid-ß in Alzheimer's disease can be affected by free transition metals such as copper and zinc in the brain. Addition of copper and zinc with amyloid acts to increase aggregation and copper additionally promotes the formation of reactive oxygen species. We propose that reduction of brain copper by blocking uptake of copper from the diet is a viable strategy to regulate the formation of insoluble amyloid-ß in the brain of Tg2576 mice. Mice were treated with regimens of zinc acetate, which acts with metallothionein to block copper uptake in the gut, at various times along their lifespan to model prevention and treatment paradigms. We found that the mice tolerated zinc acetate well over the six month course of study. While we did not observe significant changes in cognition and behavior, there was a reduction in insoluble amyloid-ß in the brain. This observation coincided with a reduction in brain copper and interestingly no change in brain zinc. Our findings show that blocking copper uptake from the diet can redistribute copper from the brain and reduce amyloid-ß aggregation.

Gender effects on plasma and brain copper.

The effect of gender on systemic and brain levels of copper is relatively understudied. We examined gender effects in mice and human subjects. We observed a trend to higher serum copper levels in female compared to male LaFerla "triple transgenic" (1399 ± 233 versus 804 ± 436 ng/mL, P = 0.06) mice, and significantly higher brain copper levels in female- versus male wild-type mice (5.2 ± 0.2 versus 4.18 ± 0.3 ng/mg wet wt, P = 0.03). Plasma copper was significantly correlated with brain copper in mice (R2 = 0.218; P = 0.038). Among human subjects with AD, both plasma copper (1284 ± 118 versus 853 ± 81 ng/mL, P = 0.005) and cerebrospinal fluid copper (12.8 ± 1 versus 10.4 ± 0.7 ng/mL, P = 0.01) were elevated in women compared to men. Among healthy control subjects, plasma copper (1008 ± 51 versus 836 ± 41 ng/mL; P = 0.01) was higher in women than in men, but there was no difference in cerebrospinal fluid copper. We conclude that gender differences in copper status may influence copper-mediated pathological events in the brain.