Lysosome-related organelles contain an expansion compartment that mediates delivery of zinc transporters to promote homeostasis.

Zinc is an essential nutrient-it is stored during periods of excess to promote detoxification and released during periods of deficiency to sustain function. Lysosome-related organelles (LROs) are an evolutionarily conserved site of zinc storage, but mechanisms that control the directional zinc flow necessary for homeostasis are not well understood. In Caenorhabditis elegans intestinal cells, the CDF-2 transporter stores zinc in LROs during excess. Here, we identify ZIPT-2.3 as the transporter that releases zinc during deficiency; ZIPT-2.3 transports zinc, localizes to the membrane of LROs in intestinal cells, and is necessary for zinc release from LROs and survival during zinc deficiency. In zinc excess and deficiency, the expression levels of CDF-2 and ZIPT-2.3 are reciprocally regulated at the level of mRNA and protein, establishing a fundamental mechanism for directional flow to promote homeostasis. To elucidate how the ratio of CDF-2 and ZIPT-2.3 is altered, we used super-resolution microscopy to demonstrate that LROs are composed of a spherical acidified compartment and a hemispherical expansion compartment. The expansion compartment increases in volume during zinc excess and deficiency. These results identify the expansion compartment as an unexpected structural feature of LROs that facilitates rapid transitions in the composition of zinc transporters to mediate homeostasis, likely minimizing the disturbance to the acidified compartment.

Fat and Dachsous cadherins in mammalian development.

Cell growth and patterning are critical for tissue development. Here we discuss the evolutionarily conserved cadherins, Fat and Dachsous, and the roles they play during mammalian tissue development and disease. In Drosophila, Fat and Dachsous regulate tissue growth via the Hippo pathway and planar cell polarity (PCP). The Drosophila wing has been an ideal tissue to observe how mutations in these cadherins affect tissue development. In mammals, there are multiple Fat and Dachsous cadherins, which are expressed in many tissues, but mutations in these cadherins that affect growth and tissue organization are context dependent. Here we examine how mutations in the Fat and Dachsous mammalian genes affect development in mammals and contribute to human disease.