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Blastocyst trophectoderm endocytic activation, a marker of adverse developmental programming

Blastocyst trophectoderm endocytic activation, a marker of adverse developmental programming
Blastocyst trophectoderm endocytic activation, a marker of adverse developmental programming

The mouse preimplantation embryo is sensitive to its environment, including maternal dietary protein restriction, which can alter the developmental programme and affect lifetime health. Previously, we have shown maternal low-protein diet (LPD) causes a reduction in blastocyst mTORC1 signalling coinciding with reduced availability of branched-chain amino acids (BCAAs) in surrounding uterine fluid. BCAA deficiency leads to increased endocytosis and lysosome biogenesis in blastocyst trophectoderm (TE), a response to promote compensatory histotrophic nutrition. Here, we first investigated the induction mechanism by individual variation in BCAA deficiency in an in vitro quantitative model of TE responsiveness. We found isoleucine (ILE) deficiency as the most effective activator of TE endocytosis and lysosome biogenesis, with less potent roles for other BCAAs and insulin; cell volume was also influential. TE response to low ILE included upregulation of vesicles comprising megalin receptor and cathepsin-B, and the response was activated from blastocyst formation. Secondly, we identified the transcription factor TFEB as mediating the histotrophic response by translocation from cytoplasm to nucleus during ILE deficiency and in response to mTORC1 inhibition. Lastly, we investigated whether a similar mechanism responsive to maternal nutritional status was found in human blastocysts. Blastocysts from women with high body-mass index, but not the method of fertilisation, revealed stimulated lysosome biogenesis and TFEB nuclear migration. We propose TE lysosomal phenotype as an early biomarker of environmental nutrient stress that may associate with long-term health outcomes.

0022-4251
289-306
Caetano, Laura
d1300a72-715f-4371-9246-92372d114584
Eckert, Judith
729bfa49-7053-458d-8e84-3e70e4d98e57
Johnston, David
b41163c9-b9d2-425c-af99-2a357204014e
Chatelet, David
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Tumbarello, David
75c6932e-fdbf-4d3c-bb4f-48fbbdba93a2
Smyth, Neil
0eba2a40-3b43-4d40-bb64-621bd7e9d505
Ingamells, Sue
b5dc3754-252a-4f67-997e-c6d7a65a566a
Price, Anthony
ae2155bc-03c4-4f60-87fd-6ccab8ebb066
Fleming, Tom
2abf761a-e5a1-4fa7-a2c8-12e32d5d4c03
Caetano, Laura
d1300a72-715f-4371-9246-92372d114584
Eckert, Judith
729bfa49-7053-458d-8e84-3e70e4d98e57
Johnston, David
b41163c9-b9d2-425c-af99-2a357204014e
Chatelet, David
6371fd7a-e274-4738-9ccb-3dd4dab32928
Tumbarello, David
75c6932e-fdbf-4d3c-bb4f-48fbbdba93a2
Smyth, Neil
0eba2a40-3b43-4d40-bb64-621bd7e9d505
Ingamells, Sue
b5dc3754-252a-4f67-997e-c6d7a65a566a
Price, Anthony
ae2155bc-03c4-4f60-87fd-6ccab8ebb066
Fleming, Tom
2abf761a-e5a1-4fa7-a2c8-12e32d5d4c03

Caetano, Laura, Eckert, Judith, Johnston, David, Chatelet, David, Tumbarello, David, Smyth, Neil, Ingamells, Sue, Price, Anthony and Fleming, Tom (2021) Blastocyst trophectoderm endocytic activation, a marker of adverse developmental programming. Reproduction, 162 (4), 289-306. (doi:10.1530/REP-21-0234).

Record type: Article

Abstract

The mouse preimplantation embryo is sensitive to its environment, including maternal dietary protein restriction, which can alter the developmental programme and affect lifetime health. Previously, we have shown maternal low-protein diet (LPD) causes a reduction in blastocyst mTORC1 signalling coinciding with reduced availability of branched-chain amino acids (BCAAs) in surrounding uterine fluid. BCAA deficiency leads to increased endocytosis and lysosome biogenesis in blastocyst trophectoderm (TE), a response to promote compensatory histotrophic nutrition. Here, we first investigated the induction mechanism by individual variation in BCAA deficiency in an in vitro quantitative model of TE responsiveness. We found isoleucine (ILE) deficiency as the most effective activator of TE endocytosis and lysosome biogenesis, with less potent roles for other BCAAs and insulin; cell volume was also influential. TE response to low ILE included upregulation of vesicles comprising megalin receptor and cathepsin-B, and the response was activated from blastocyst formation. Secondly, we identified the transcription factor TFEB as mediating the histotrophic response by translocation from cytoplasm to nucleus during ILE deficiency and in response to mTORC1 inhibition. Lastly, we investigated whether a similar mechanism responsive to maternal nutritional status was found in human blastocysts. Blastocysts from women with high body-mass index, but not the method of fertilisation, revealed stimulated lysosome biogenesis and TFEB nuclear migration. We propose TE lysosomal phenotype as an early biomarker of environmental nutrient stress that may associate with long-term health outcomes.

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More information

Accepted/In Press date: 30 July 2021
e-pub ahead of print date: 1 August 2021
Published date: October 2021
Additional Information: Funding Information: This work was supported through the Rosetrees Trust (A798), the Biotechnology and Biological Sciences Research Council (BBSRC) (BB/F007450/1) and the University of Southampton to T P F. Publisher Copyright: © 2021 Society for Reproduction and Fertility

Identifiers

Local EPrints ID: 450554
URI: http://eprints.soton.ac.uk/id/eprint/450554
ISSN: 0022-4251
PURE UUID: fa4348ba-12bc-43ec-9c3a-6170f8e9d4cc
ORCID for David Johnston: ORCID iD orcid.org/0000-0001-6703-6014
ORCID for David Tumbarello: ORCID iD orcid.org/0000-0002-5169-0561

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Date deposited: 03 Aug 2021 16:32
Last modified: 17 Mar 2024 03:35

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Contributors

Author: Laura Caetano
Author: Judith Eckert
Author: David Johnston ORCID iD
Author: David Chatelet
Author: Neil Smyth
Author: Sue Ingamells
Author: Anthony Price
Author: Tom Fleming

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