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Shriver, L.

Publications and source records attributed to Shriver, L..

3 recordsLinked to original sources

Cell type diversification and phenotype convergence underlying white fin-ornamentation of cyprinid fishes

Neural crest derived cells offer valuable opportunities to dissect mechanisms of cell fate specification and differentiation within individual ontogenies and the underpinnings of cell type diversification over evolutionary time. Particularly useful for such analyses are pigment cells of ectothermic vertebrates that arise from neural crest cells, or via latent neural crest derived stem cells, and comprise several classes with cell-type specific pigmentary phenotypes. Among these are white cells, "leucophores," present in a variety of species that contribute to patterns on the body or ornamentation on the fins. To better understand developmental and evolutionary origins of these cells we have examined leucophores harboring deposits of yellow/orange carotenoids, "xantholeucophores," of zebrafish and leucophores of white cloud minnow, within the same family Cyprinidae. We show that white phenotypes of both cell types require sepiapterin reductase that promotes accumulation of pale and colorless pteridines. We further demonstrate that xantholeucophores develop directly from yellow sepiapterin rich xanthophore-like cells and that this transition requires both gap junctional activity and permeability of the aquaglyceroporin / peroxiporin channel Aquaporin 3. These findings identify these white cells as distinct developmentally, genetically, and biochemically from another type of white cell in zebrafish and other white cells present across phylogenetic lineages. Our results highlight remarkable convergences and parallelisms in the acquisition of white cell phenotypes within and between species and identify this as a rich system for enquiries into the evolutionary individuation of novel cell types. SignificanceUnderstanding how cell types arise is fundamental to explaining animal complexity. Pigment cells offer opportunities to address this question because they display striking variation. We show that white pigment cells comprise multiple classes with independent origins. In zebrafish, white cells on one fin develop from melanophores whereas white cells on another fin develop from yellow precursors that convert their pigments to colorless ones. White cells of a related minnow require the same colorless pigments yet differ in other ways. These findings illuminate remarkable convergence: white cells have arisen repeatedly from different progenitor cell lineages by different mechanisms. This diversity--even within and between closely related species--identifies a powerful model for understanding the evolution of cell types with distinct identities and functions.

developmental biology↗

Mitochondrial pyruvate transport regulates presynaptic metabolism and neurotransmission

Glucose has long been considered the primary fuel source for the brain. However, glucose levels fluctuate in the brain during sleep, intense circuit activity, or dietary restrictions, posing significant metabolic stress. Here, we demonstrate that the mammalian brain utilizes pyruvate as a fuel source, and pyruvate can support neuronal viability in the absence of glucose. Nerve terminals are sites of metabolic vulnerability within a neuron and we show that mitochondrial pyruvate uptake is a critical step in oxidative ATP production in hippocampal terminals. We find that the mitochondrial pyruvate carrier is post-translationally modified by lysine acetylation which in turn modulates mitochondrial pyruvate uptake. Importantly, our data reveal that the mitochondrial pyruvate carrier regulates distinct steps in synaptic transmission, namely, the spatiotemporal pattern of synaptic vesicle release and the efficiency of vesicle retrieval, functions that have profound implications for synaptic plasticity. In summary, we identify pyruvate as a potent neuronal fuel and mitochondrial pyruvate uptake as a critical node for the metabolic control of synaptic transmission in hippocampal terminals. HIGHLIGHTSO_LISerum pyruvate is taken up by the brain and efficiently oxidized in the TCA cycle. C_LIO_LIThe mitochondrial pyruvate carrier (MPC) is essential for presynaptic energy metabolism. C_LIO_LIAcetylation of the MPC complex modulates mitochondrial pyruvate uptake. C_LIO_LIMPC activity regulates the release and retrieval of synaptic vesicles in nerve terminals. C_LI

neuroscience↗

Targeting fatty acid beta-oxidation impairs monocyte differentiation and prolongs heart allograft survival

AO_SCPLOWBSTRACTC_SCPLOWMonocytes play an important role in the regulation of alloimmune responses after heart transplantation (HTx). Recent studies have highlighted the importance of immunometabolism in the differentiation and function of myeloid cells. While the importance of glucose metabolism in monocyte differentiation and function has been reported, a role for fatty acid {beta}-oxidation (FAO) has not been explored. Heterotopic HTx was performed using hearts from Balb/c donor mice implanted into C57Bl/6 recipient mice and treated with etomoxir (eto), an irreversible inhibitor of carnitine palmitoyltransferase 1 (Cpt1), a rate-limiting step of FAO, or vehicle control. FAO inhibition prolonged HTx survival, reduced early T cell infiltration/ activation and reduced dendritic cell (DC) and macrophage infiltration to heart allografts of eto-treated HTx recipients. ELISPOT demonstrated eto-treated HTx were less reactive to activated donor antigen presenting cells. FAO inhibition reduced monocyte-to-DC and monocyte-to-macrophage differentiation in vitro and in vivo. Further, FAO inhibition did not alter the survival of heart allografts when transplanted into Ccr2-deficient recipients, suggesting the effects of FAO inhibition on reduced immune cell infiltration and increased heart allograft survival were dependent on monocyte mobilization. Finally, we confirmed the importance of FAO on monocyte differentiation in vivo using conditional deletion of Cpt1a. Our findings demonstrate that targeting FAO attenuates alloimmunity after HTx, in part through impairing monocyte differentiation.

immunology↗