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1.
Dev Cell ; 56(8): 1182-1194.e6, 2021 04 19.
Article in English | MEDLINE | ID: mdl-33773101

ABSTRACT

Pyruvate dehydrogenase kinases (PDK1-4) inhibit the TCA cycle by phosphorylating pyruvate dehydrogenase complex (PDC). Here, we show that PDK family is dispensable for murine embryonic development and that BCKDK serves as a compensatory mechanism by inactivating PDC. First, we knocked out all four Pdk genes one by one. Surprisingly, Pdk total KO embryos developed and were born in expected ratios but died by postnatal day 4 because of hypoglycemia or ketoacidosis. Moreover, PDC was phosphorylated in these embryos, suggesting that another kinase compensates for PDK family. Bioinformatic analysis implicated branched-chain ketoacid dehydrogenase kinase (Bckdk), a key regulator of branched-chain amino acids (BCAAs) catabolism. Indeed, knockout of Bckdk and Pdk family led to the loss of PDC phosphorylation, an increase in PDC activity and pyruvate entry into the TCA cycle, and embryonic lethality. These findings reveal a regulatory crosstalk hardwiring BCAA and glucose catabolic pathways, which feed the TCA cycle.


Subject(s)
Citric Acid Cycle , Embryonic Development , Protein Kinases/metabolism , Pyruvate Dehydrogenase Acetyl-Transferring Kinase/metabolism , Pyruvate Dehydrogenase Complex/metabolism , Animals , Animals, Newborn , Embryo Loss/enzymology , Embryo Loss/pathology , Gene Deletion , Hypoglycemia/complications , Hypoglycemia/enzymology , Hypoglycemia/pathology , Ketosis/complications , Ketosis/enzymology , Ketosis/pathology , Mice, Knockout , Models, Biological , Phosphorylation , Pyruvic Acid/metabolism
2.
Development ; 144(21): 3855-3866, 2017 11 01.
Article in English | MEDLINE | ID: mdl-29089359

ABSTRACT

During development, genes are transcribed at specific times, locations and levels. In recent years, the emergence of quantitative tools has significantly advanced our ability to measure transcription with high spatiotemporal resolution in vivo Here, we highlight recent studies that have used these tools to characterize transcription during development, and discuss the mechanisms that contribute to the precision and accuracy of the timing, location and level of transcription. We attempt to disentangle the discrepancies in how physicists and biologists use the term 'precision' to facilitate interactions using a common language. We also highlight selected examples in which the coupling of mathematical modeling with experimental approaches has provided important mechanistic insights, and call for a more expansive use of mathematical modeling to exploit the wealth of quantitative data and advance our understanding of animal transcription.


Subject(s)
Models, Biological , Transcription, Genetic , Animals , Embryonic Development/genetics , Gene Expression Regulation, Developmental , Time Factors
3.
Development ; 139(23): 4473-83, 2012 Dec 01.
Article in English | MEDLINE | ID: mdl-23095889

ABSTRACT

Collagen production is fundamental for the ontogeny and the phylogeny of all multicellular organisms. It depends on hydroxylation of proline residues, a reaction that uses molecular oxygen as a substrate. This dependency is expected to limit collagen production to oxygenated cells. However, during embryogenesis, cells in different tissues that develop under low oxygen levels must produce this essential protein. In this study, using the growth plate of developing bones as a model system, we identify the transcription factor hypoxia-inducible factor 1 α (HIF1α) as a central component in a mechanism that underlies collagen hydroxylation and secretion by hypoxic cells. We show that Hif1a loss of function in growth plate chondrocytes arrests the secretion of extracellular matrix proteins, including collagen type II. Reduced collagen hydroxylation and endoplasmic reticulum stress induction in Hif1a-depleted cells suggests that HIF1α regulates collagen secretion by mediating its hydroxylation and consequently its folding. We demonstrate in vivo the ability of Hif1α to drive the transcription of collagen prolyl 4-hydroxylase, which catalyzes collagen hydroxylation. We also show that, concurrently, HIF1α maintains cellular levels of oxygen, most likely by controlling the expression of pyruvate dehydrogenase kinase 1, an inhibitor of the tricarboxylic acid cycle. Through this two-armed mechanism, HIF1α acts as a central regulator of collagen production that allows chondrocytes to maintain their function as professional secretory cells in the hypoxic growth plate. As hypoxic conditions occur also during pathological conditions such as cancer, our findings may promote the understanding not only of embryogenesis, but also of pathological processes.


Subject(s)
Bone and Bones/embryology , Cell Hypoxia , Chondrocytes/metabolism , Collagen/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Animals , Bone Development , Cells, Cultured , Citric Acid Cycle , Endoplasmic Reticulum , Growth Plate/metabolism , Hydroxylation , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Mice , Oxygen/metabolism , Procollagen-Proline Dioxygenase/biosynthesis , Procollagen-Proline Dioxygenase/genetics , Procollagen-Proline Dioxygenase/metabolism , Protein Folding , Protein Serine-Threonine Kinases/biosynthesis , Pyruvate Dehydrogenase Acetyl-Transferring Kinase
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