# NIH grant: Control of Developmental Timing by NADH Redox Metabolism (1R01HD120311-01) — retained record

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[original source ↗](https://reporter.nih.gov/project-details/1R01HD120311-01)

## retained text



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NIH grant 1R01HD120311-01: Control of Developmental Timing by NADH Redox Metabolism
Institute: {'code': 'HD', 'abbreviation': 'NICHD', 'name': 'Eunice Kennedy Shriver National Institute of Child Health and Human Development', 'admin_org_id': '12500030', 'admin_funding_url': ''}. PI: Margarete  Diaz Cuadros. Award: $538173.
Start: 2026-08-01T00:00:00.
PROJECT SUMMARY
Proper embryonic development requires the precise orchestration of a series of well-conserved developmental
steps in both space and time. Defects in the temporal unfolding of these steps can give rise to congenital
diseases. Surprisingly, the speed of embryonic development is highly species-specific. For instance, among
mammals, the duration of embryogenesis ranges from 15 days in mice to 116 days in elephants.
Understanding how these species-specific developmental rates are set could have significant translational
potential, including accelerating stem cell differentiation for cell therapies or decelerating cellular processes to
combat tumor growth and aging. To precisely measure developmental speed across species, we rely on the
segmentation clock, a molecular oscillator whose period tightly correlates with the duration of embryogenesis.
We have recapitulated the segmentation clock in vitro using mouse and human pluripotent stem cells,
therefore enabling cross-species comparisons. Using this experimental platform, we recently found that a key
factor regulating developmental speed is the cytosolic NAD+/NADH ratio. This parameter was elevated in
mouse cells (fast-developing) compared to human cells (slow-developing). Moreover, experimentally lowering
the NAD+/NADH ratio slowed down the segmentation clock, whereas its increase resulted in acceleration.
Here we propose to identify the mechanisms that give rise to differential cytosolic NAD+/NADH ratios between
species. Cytosolic redox balance is known to be regulated by NADH shuttling systems that oxidize NADH in
the cytosol and transfer the reducing equivalents to the mitochondria. Two primary NADH shuttles exist: the
glycerol-3-phosphate (G3P) and the malate-aspartate (MA) shuttle. Preliminary data suggest that the G3P
shuttle is more active in mouse embryonic cells than in human cells due to differential expression of shuttle
enzymes. We hypothesize that species-specific expression of G3P shuttle components in mouse and human
embryonic cells drives differences in G3P shuttle activity, thereby establishing distinct cytosolic NAD+/NADH
ratios and contributing to the disparity in developmental speed between these two species. In Aim 1, we will
directly test the role of NADH shuttles in establishing species-specific NAD+/NADH ratios by comparing shuttle
fluxes between mouse and human embryonic cell types, and by manipulating the expression of shuttle
components. In Aim 2, we will investigate the regulatory mechanisms underlying species-specific expression of
NADH shuttle components, particularly GPD1L, a key enzyme in the G3P shuttle which is expressed in mouse
cells but not human cells. By identifying the cis- and trans-regulatory elements controlling species-specific
GPD1L expression, we will begin to uncover the genetic basis for differences in developmental speed between
species. Overall, the proposed research will provide critical insights into species-specific developmental timing
and enhance the utility of human stem cells for therapeutic applications by devising novel strategies for the
acceleration of developmental rate.
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