Cortical morphology at birth reflects spatio-temporal patterns of gene expression in the fetal brain

Ball, G.; Seidlitz, J.; O'Muircheartaigh, J.; Dimitrova, R.; Fenchel, D.; Makropoulos, A.; Christiaens, D.; Schuh, A.; Passerat-Palmbach, J.; Cordero-Grande, L.; Hughes, E.; Price, A.; Hajnal, J. V.; Rueckert, D.; Robinson, E. C.; Edwards, D.

doi:10.1101/2020.01.28.922849

bioRxiv · 10.1101/2020.01.28.922849

Cortical morphology at birth reflects spatio-temporal patterns of gene expression in the fetal brain

Ball, G.·Seidlitz, J.·O'Muircheartaigh, J.·Dimitrova, R.·Fenchel, D.·Makropoulos, A.·Christiaens, D.·Schuh, A.·Passerat-Palmbach, J.·Cordero-Grande, L.·Hughes, E.·Price, A.·Hajnal, J. V.·Rueckert, D.·Robinson, E. C.·Edwards, D.

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Abstract

Interruption to gestation through preterm birth can significantly impact cortical development and have long-lasting adverse effects on neurodevelopmental outcome. We compared cortical morphology captured by high-resolution, multimodal MRI in n=292 healthy newborn infants (mean age at birth=39.9 weeks) with regional patterns of gene expression in the fetal cortex across gestation (n=156 samples from 16 brains, aged 12 to 37 post-conceptional weeks). We tested the hypothesis that noninvasive measures of cortical structure at birth mirror areal differences in cortical gene expression across gestation, and in a cohort of n=64 preterm infants (mean age at birth = 32.0 weeks), we tested whether cortical alterations observed after preterm birth were associated with altered gene expression in specific developmental cell populations. Neonatal cortical structure was aligned to differential patterns of cell-specific gene expression in the fetal cortex. Principal component analysis of six measures of cortical morphology and microstructure showed that cortical regions were ordered along a principal axis, with primary cortex clearly separated from heteromodal cortex. This axis was correlated to estimated tissue maturity, indexed by differential expression of genes expressed by progenitor cells and neurons; and engaged in stem cell differentiation, neuron migration and forebrain development. Preterm birth was associated with altered regional MRI metrics and patterns of differential gene expression in glial cell populations. The spatial patterning of gene expression in the developing cortex was thus mirrored by regional variation in cortical morphology and microstructure at term, and this was disrupted by preterm birth. This work provides a framework to link molecular mechanisms to noninvasive measures of cortical development in early life and highlights novel pathways to injury in neonatal populations at increased risk of neurodevelopmental disorder.

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Ball, G., Seidlitz, J., O'Muircheartaigh, J., Dimitrova, R., Fenchel, D., Makropoulos, A., Christiaens, D., Schuh, A., Passerat-Palmbach, J., Cordero-Grande, L., Hughes, E., Price, A., Hajnal, J. V., Rueckert, D., Robinson, E. C., Edwards, D.. 2020-01-29. Cortical morphology at birth reflects spatio-temporal patterns of gene expression in the fetal brain. https://doi.org/10.1101/2020.01.28.922849

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