Experimental test of the influence of light availability on the evolution of eye size and behaviour in Daphnia.

There exists extensive variation in eye size. Much work has provided a connection between light availability and differences in eye size across taxa. Experimental tests of the role of the light environment on the evolution of eye size are lacking. Here, we performed a selection experiment that examined the influence of light availability on shifts in eye size and the connection between eye size and phototactic (anti-predator) behaviour in Daphnia. We set-up replicate experimental populations of Daphnia, repeatedly evaluated phenotypic shifts in eye size during the ~50-day experiment, and performed a common garden experiment at the end of the experiment to test for evolutionary shifts in eye size and behaviour. Our phenotypic analyses showed that eye size rapidly diverged between the light treatments; relative eye size was consistently larger in the low versus high light treatments. Selection on eye size was also modified by variation in density as increases in Daphnia density favoured a larger eye. However, we did not observe differences in eye size between the light treatments following two generations of common garden rearing at the end of the experiment. We instead observed strong shifts in anti-predator behaviour. Daphnia from the low light treatment exhibited decreased phototactic responses to light. Our results show that decreased light relaxes selection on anti-predator behaviour. Such trends provide new insights into selection on eye size and behaviour.

Ascorbate depletion increases quiescence and self-renewal potential in hematopoietic stem cells and multipotent progenitors.

Ascorbate (vitamin C) limits hematopoietic stem cell (HSC) function and suppresses leukemia development by promoting the function of the Tet2 tumor suppressor. In humans, ascorbate is obtained from the diet while in mice it is synthesized in the liver. In this study, we show that deletion of the Slc23a2 ascorbate transporter severely depleted ascorbate from hematopoietic cells. Slc23a2 deficiency increased HSC reconstituting potential and self-renewal potential upon transplantation into irradiated mice. Slc23a2 deficiency also increased the reconstituting and self-renewal potential of multipotent hematopoietic progenitors (MPPs), conferring the ability to long-term reconstitute irradiated mice. Slc23a2-deficient HSCs and MPPs divided much less frequently than control HSCs and MPPs. Increased self-renewal and reconstituting potential were observed particularly in quiescent Slc23a2-deficient HSCs and MPPs. The effect of Slc23a2 deficiency on MPP self-renewal was not mediated by reduced Tet2 function. Ascorbate thus regulates quiescence and restricts self-renewal potential in HSCs and MPPs such that ascorbate depletion confers MPPs with long-term self-renewal potential.

A Short Isoform of Spermatogenic Enzyme GAPDHS Functions as a Metabolic Switch and Limits Metastasis in Melanoma.

Despite being the leading cause of cancer deaths, metastasis remains a poorly understood process. To identify novel regulators of metastasis in melanoma, we performed a large-scale RNA sequencing screen of 48 samples from patient-derived xenograft (PDX) subcutaneous melanomas and their associated metastases. In comparison with primary tumors, expression of glycolytic genes was frequently decreased in metastases, whereas expression of some tricarboxylic acid (TCA) cycle genes was increased in metastases. Consistent with these transcriptional changes, melanoma metastases underwent a metabolic switch characterized by decreased levels of glycolytic metabolites and increased abundance of TCA cycle metabolites. A short isoform of glyceraldehyde-3-phosphate dehydrogenase, spermatogenic (GAPDHS) lacking the N-terminal domain suppressed metastasis and regulated this metabolic switch. GAPDHS was downregulated in metastatic nodules from PDX models as well as in human patients. Overexpression of GAPDHS was sufficient to block melanoma metastasis, whereas its inhibition promoted metastasis, decreased glycolysis, and increased levels of certain TCA cycle metabolites and their derivatives including citrate, fumarate, malate, and aspartate. Isotope tracing studies indicated that GAPDHS mediates this shift through changes in pyruvate carboxylase activity and aspartate synthesis, both metabolic pathways critical for cancer survival and metastasis. Together, these data identify a short isoform of GAPDHS that limits melanoma metastasis and regulates central carbon metabolism. SIGNIFICANCE: This study characterizes metabolic changes during cancer metastasis and identifies GAPDHS as a novel regulator of these processes in melanoma cells.