A diffusion MRI-based spatiotemporal continuum of the embryonic mouse brain for probing gene-neuroanatomy connections

Dan Wu; Linda J Richards; Zhiyong Zhao; Zuozhen Cao; Wanrong Luo; Wei Shao; Song-Hai Shi; Michael I Miller; Susumu Mori; Seth Blackshaw; Jiangyang Zhang

doi:10.1073/pnas.2111869119

A diffusion MRI-based spatiotemporal continuum of the embryonic mouse brain for probing gene-neuroanatomy connections

Proc Natl Acad Sci U S A. 2022 Feb 15;119(7):e2111869119. doi: 10.1073/pnas.2111869119.

Authors

Dan Wu^{1

2

3}, Linda J Richards⁴, Zhiyong Zhao⁵, Zuozhen Cao⁵, Wanrong Luo⁵, Wei Shao⁶, Song-Hai Shi^{6

7}, Michael I Miller^{8

9

10}, Susumu Mori^{11

12}, Seth Blackshaw^{13

14

15

16

17}, Jiangyang Zhang¹⁸

Affiliations

¹ Key Laboratory for Biomedical Engineering of Ministry of Education, Department of Biomedical Engineering, College of Biomedical Engineering & Instrument Science, Zhejiang University, Hangzhou 310027, China; danwu.bme@zju.edu.cn jiangyang.zhang@nyulangone.org.
² Department of Neurology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China.
³ Binjiang Institute of Zhejiang University, Hangzhou 310053, China.
⁴ McDonnell Center for Cellular & Molecular Neurobiology, Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110.
⁵ Key Laboratory for Biomedical Engineering of Ministry of Education, Department of Biomedical Engineering, College of Biomedical Engineering & Instrument Science, Zhejiang University, Hangzhou 310027, China.
⁶ Developmental Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
⁷ International Data Group (IDG)/McGovern Institute for Brain Research, Tsinghua-Peking Center for Life Sciences, Beijing Frontier Research Center for Biological Structure, Beijing Advanced Innovation Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China.
⁸ Department of Biomedicine Engineering, Johns Hopkins University, Baltimore, MD 21218.
⁹ Center of Imaging Science, Johns Hopkins University, Baltimore, MD 21218.
¹⁰ Institute for Computational Medicine, Johns Hopkins University, Baltimore, MD 21218.
¹¹ Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
¹² F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD 21205.
¹³ Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
¹⁴ Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
¹⁵ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
¹⁶ Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
¹⁷ Kavli Neuroscience Discovery Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
¹⁸ Department of Radiology, NYU Langone School of Medicine, New York, NY 10016 danwu.bme@zju.edu.cn jiangyang.zhang@nyulangone.org.

Abstract

The embryonic mouse brain undergoes drastic changes in establishing basic anatomical compartments and laying out major axonal connections of the developing brain. Correlating anatomical changes with gene-expression patterns is an essential step toward understanding the mechanisms regulating brain development. Traditionally, this is done in a cross-sectional manner, but the dynamic nature of development calls for probing gene-neuroanatomy interactions in a combined spatiotemporal domain. Here, we present a four-dimensional (4D) spatiotemporal continuum of the embryonic mouse brain from E10.5 to E15.5 reconstructed from diffusion magnetic resonance microscopy (dMRM) data. This study achieved unprecedented high-definition dMRM at 30- to 35-µm isotropic resolution, and together with computational neuroanatomy techniques, we revealed both morphological and microscopic changes in the developing brain. We transformed selected gene-expression data to this continuum and correlated them with the dMRM-based neuroanatomical changes in embryonic brains. Within the continuum, we identified distinct developmental modes comprising regional clusters that shared developmental trajectories and similar gene-expression profiles. Our results demonstrate how this 4D continuum can be used to examine spatiotemporal gene-neuroanatomical interactions by connecting upstream genetic events with anatomical changes that emerge later in development. This approach would be useful for large-scale analysis of the cooperative roles of key genes in shaping the developing brain.

Keywords: developmental mode; diffusion MR microscopy; embryonic mouse brain; gene expression; spatiotemporal continuum.

MeSH terms

Animals
Brain / embryology*
Brain / metabolism
Computer Simulation
Embryo, Mammalian / metabolism*
Embryonic Development / physiology*
Gene Expression Regulation, Developmental / physiology*
Magnetic Resonance Imaging / methods*
Mice
Models, Biological

Abstract

MeSH terms

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