No abstract

The copper-translocating Menkes (ATP7A, MNK protein) and Wilson (ATP7B, WND protein) P-type ATPases are pivotal for copper (Cu) homeostasis, functioning in the biosynthetic incorporation of Cu into copper-dependent enzymes of the secretory pathway, Cu detoxification via Cu efflux, and specialized roles such as systemic Cu absorption (MNK) and Cu excretion (WND). Essential to these functions is their Cu and hormone-responsive distribution between the trans-Golgi network (TGN) and exocytic vesicles located at or proximal to the apical (WND) or basolateral (MNK) cell surface. Intriguingly, MNK and WND Cu-ATPases expressed in the same tissues perform distinct yet complementary roles. While intramolecular differences may specify their distinct roles, cellular signaling components are predicted to be critical for both differences and synergy between these enzymes. This review focuses on these mechanisms, including the cell signaling pathways that influence trafficking and bi-functionality of Cu-ATPases. Phosphorylation events are hypothesized to play a central role in Cu homeostasis, promoting multi-layered regulation and cross-talk between cuproenzymes and Cu-independent mechanisms.

Elephants have the longest pregnancy of all mammals, with an average gestation of around 660 days, so their embryonic and foetal development have always been of special interest. Hitherto, it has only been possible to estimate foetal ages from theoretical calculations based on foetal mass. The recent development of sophisticated ultrasound procedures for elephants has now made it possible to monitor the growth and development of foetuses of known gestational age conceived in captivity from natural matings or artificial insemination. We have studied the early stages of pregnancy in 10 captive Asian and 9 African elephants by transrectal ultrasound. Measurements of foetal crown-rump lengths have provided the first accurate growth curves, which differ significantly from the previous theoretical estimates based on the cube root of foetal mass. We have used these to age 22 African elephant foetuses collected during culling operations. Pregnancy can be first recognized ultrasonographically by day 50, the presumptive yolk sac by about day 75 and the zonary placenta by about day 85. The trunk is first recognizable by days 85-90 and is distinct by day 104, while the first heartbeats are evident from around day 80. By combining ultrasonography and morphology, we have been able to produce the first reliable criteria for estimating gestational age and ontological development of Asian and African elephant foetuses during the first third of gestation.

The early embryology of the elephant has never been studied before. We have obtained a rare series of African elephant (Loxodonta africana) embryos and fetuses ranging in weight from 0.04 to 18.5 g, estimated gestational ages 58-166 days (duration of gestation is Ϸ660 days). Nephrostomes, a feature of aquatic vertebrates, were found in the mesonephric kidneys at all stages of development whereas they have never been recorded in the mesonephric kidneys of other viviparous mammals. The trunk was well developed even in the earliest fetus. The testes were intra-abdominal, and there was no evidence of a gubernaculum, pampiniform plexus, processus vaginalis, or a scrotum, confirming that the elephant, like the dugong, is one of the few primary testicond mammals. The palaeontological evidence suggests that the elephant's ancestors were aquatic, and recent immunological and molecular evidence shows an extremely close affinity between present-day elephants and the aquatic Sirenia (dugong and manatees). The evidence from our embryological study of the elephant also suggests that it evolved from an aquatic mammal.