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Cell Rep. 2016 Oct 18;17(4):1022-1036. doi: 10.1016/j.celrep.2016.09.067.

A Glo1-Methylglyoxal Pathway that Is Perturbed in Maternal Diabetes Regulates Embryonic and Adult Neural Stem Cell Pools in Murine Offspring.

Author information

1
Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
2
Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Institute of Medical Science, University of Toronto, Toronto, ON M5G 1A8, Canada.
3
Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Physiology, University of Toronto, Toronto, ON M5G 1A8, Canada.
4
Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Physiology, University of Toronto, Toronto, ON M5G 1A8, Canada; Department of Psychology, University of Toronto, Toronto, ON M5G 1A8, Canada; Institute of Medical Science, University of Toronto, Toronto, ON M5G 1A8, Canada.
5
Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1A8, Canada; Institute of Medical Science, University of Toronto, Toronto, ON M5G 1A8, Canada. Electronic address: dkaplan@sickkids.ca.
6
Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Physiology, University of Toronto, Toronto, ON M5G 1A8, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1A8, Canada; Institute of Medical Science, University of Toronto, Toronto, ON M5G 1A8, Canada. Electronic address: fredam@sickkids.ca.

Abstract

Maternal diabetes is known to adversely influence brain development in offspring. Here, we provide evidence that this involves the circulating metabolite methylglyoxal, which is increased in diabetes, and its detoxifying enzyme, glyoxalase 1 (Glo1), which when mutated is associated with neurodevelopmental disorders. Specifically, when Glo1 levels were decreased in embryonic mouse cortical neural precursor cells (NPCs), this led to premature neurogenesis and NPC depletion embryonically and long-term alterations in cortical neurons postnatally. Increased circulating maternal methylglyoxal caused similar changes in embryonic cortical precursors and neurons and long-lasting changes in cortical neurons and NPCs in adult offspring. Depletion of embryonic and adult NPCs was also observed in murine offspring exposed to a maternal diabetic environment. Thus, the Glo1-methylglyoxal pathway integrates maternal and NPC metabolism to regulate neural development, and perturbations in this pathway lead to long-lasting alterations in adult neurons and NPC pools.

KEYWORDS:

Glyoxalase 1; autism spectrum disorder; cortical development; maternal diabetes; methylglyoxal; neural stem cells; neurodevelopmental disorders; neurogenesis

PMID:
27760310
DOI:
10.1016/j.celrep.2016.09.067
[Indexed for MEDLINE]
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