Cortical morphology at birth reflects spatiotemporal patterns of gene expression in the fetal human brain

Gareth Ball; Jakob Seidlitz; Jonathan O’Muircheartaigh; Ralica Dimitrova; Daphna Fenchel; Antonios Makropoulos; Daan Christiaens; Andreas Schuh; Jonathan Passerat-Palmbach; Jana Hutter; Lucilio Cordero-Grande; Emer Hughes; Anthony Price; Jo V. Hajnal; Daniel Rueckert; Emma C. Robinson; A. David Edwards

doi:10.1371/journal.pbio.3000976

Cortical morphology at birth reflects spatiotemporal patterns of gene expression in the fetal human brain

Gareth Ball^*, Jakob Seidlitz, Jonathan O’Muircheartaigh, Ralica Dimitrova, Daphna Fenchel, Antonios Makropoulos, Daan Christiaens, Andreas Schuh, Jonathan Passerat-Palmbach, Jana Hutter, Lucilio Cordero-Grande, Emer Hughes, Anthony Price, Jo V. Hajnal, Daniel Rueckert, Emma C. Robinson, A. David Edwards

^*Corresponding author for this work

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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 magnetic resonance imaging (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 postconceptional weeks [pcw]). 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 (PCA) of 6 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 with 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.

Original language	English
Article number	e3000976
Journal	PLoS Biology
Volume	18
Issue number	11
Early online date	23 Nov 2020
DOIs	https://doi.org/10.1371/journal.pbio.3000976
Publication status	E-pub ahead of print - 23 Nov 2020

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Ball_PlosBIO_acceptedAccepted author manuscript, 935 KBLicence: CC BY

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Ball, G., Seidlitz, J., O’Muircheartaigh, J., Dimitrova, R., Fenchel, D., Makropoulos, A., Christiaens, D., Schuh, A., Passerat-Palmbach, J., Hutter, J., Cordero-Grande, L., Hughes, E., Price, A., Hajnal, J. V., Rueckert, D., Robinson, E. C., & Edwards, A. D. (2020). Cortical morphology at birth reflects spatiotemporal patterns of gene expression in the fetal human brain. PLoS Biology, 18(11), [e3000976]. https://doi.org/10.1371/journal.pbio.3000976

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title = "Cortical morphology at birth reflects spatiotemporal patterns of gene expression in the fetal human brain",

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 magnetic resonance imaging (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 postconceptional weeks [pcw]). 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 (PCA) of 6 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 with 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.",

author = "Gareth Ball and Jakob Seidlitz and Jonathan O{\textquoteright}Muircheartaigh and Ralica Dimitrova and Daphna Fenchel and Antonios Makropoulos and Daan Christiaens and Andreas Schuh and Jonathan Passerat-Palmbach and Jana Hutter and Lucilio Cordero-Grande and Emer Hughes and Anthony Price and Hajnal, {Jo V.} and Daniel Rueckert and Robinson, {Emma C.} and Edwards, {A. David}",

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Ball, G, Seidlitz, J, O’Muircheartaigh, J, Dimitrova, R, Fenchel, D, Makropoulos, A, Christiaens, D, Schuh, A, Passerat-Palmbach, J, Hutter, J , Cordero-Grande, L, Hughes, E, Price, A, Hajnal, JV, Rueckert, D, Robinson, EC & Edwards, AD 2020, 'Cortical morphology at birth reflects spatiotemporal patterns of gene expression in the fetal human brain', PLoS Biology, vol. 18, no. 11, e3000976. https://doi.org/10.1371/journal.pbio.3000976

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AU - Ball, Gareth

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AU - Fenchel, Daphna

AU - Makropoulos, Antonios

AU - Christiaens, Daan

AU - Schuh, Andreas

AU - Passerat-Palmbach, Jonathan

AU - Hutter, Jana

AU - Cordero-Grande, Lucilio

AU - Hughes, Emer

AU - Price, Anthony

AU - Hajnal, Jo V.

AU - Rueckert, Daniel

AU - Robinson, Emma C.

AU - Edwards, A. David

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N2 - 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 magnetic resonance imaging (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 postconceptional weeks [pcw]). 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 (PCA) of 6 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 with 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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Cortical morphology at birth reflects spatiotemporal patterns of gene expression in the fetal human brain

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