The new frontier in understanding human and mammalian brain development

Tomasz J Nowakowski^{1

2

3

4

5

6}, Patricia R Nano⁷, Katherine S Matho^{8

9}, Xiaoyin Chen¹⁰, Emily K Corrigan^{11

12}, Wubin Ding¹³, Yuan Gao¹⁰, Matthew Heffel^{14

15}, Jaikishan Jayakumar¹⁶, Harris S Kaplan^{17

18

19}, Fae N Kronman²⁰, Rothem Kovner²¹, Camiel C A Mannens^{22

23

24

25}, Mengyi Song^{11

12}, Marilyn R Steyert^{26

27

28

11

29

30}, Sridevi Venkatesan³¹, Jenelle L Wallace^{11

29

12}, Li Wang^{11

12}, Jonathan M Werner^{31

32}, Di Zhang³³, Guohua Yuan^{26

27

28

11

29

30}, Guolong Zuo^{11

12}, Seth A Ament^{32

34}, Carlo Colantuoni^{32

35}, Catherine Dulac^{17

18

19}, Rong Fan³³, Jesse Gillis³¹, Arnold R Kriegstein^{11

29

30

12}, Fenna M Krienen³⁶, Yongsoo Kim²⁰, Sten Linnarsson²², Partha P Mitra³⁷, Alex A Pollen^{11

29

30

12}, Nenad Sestan²¹, Daniel J Tward^{38

39}, Cindy T J van Velthoven¹⁰, Zizhen Yao¹⁰, Aparna Bhaduri⁴⁰, Hongkui Zeng^{41

42}

Affiliations

¹ Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA. Tomasz.nowakowski@ucsf.edu.
² Department of Anatomy, University of California San Francisco, San Francisco, CA, USA. Tomasz.nowakowski@ucsf.edu.
³ Department of Psychiatry and Behavioral Sciences, University of California San Francisco, San Francisco, CA, USA. Tomasz.nowakowski@ucsf.edu.
⁴ The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, CA, USA. Tomasz.nowakowski@ucsf.edu.
⁵ Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA. Tomasz.nowakowski@ucsf.edu.
⁶ Kavli Institute for Fundamental Neuroscience, University of California San Francisco, San Francisco, CA, USA. Tomasz.nowakowski@ucsf.edu.
⁷ Department of Biological Chemistry, University of California Los Angeles, Los Angeles, CA, USA.
⁸ Children's Hospital Los Angeles, Los Angeles, CA, USA.
⁹ Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
¹⁰ Allen Institute for Brain Science, Seattle, WA, USA.
¹¹ The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, CA, USA.
¹² Department of Neurology, University of California San Francisco, San Francisco, CA, USA.
¹³ Genomic Analysis Laboratory, The Salk Institute for Biological Studies, La Jolla, CA, USA.
¹⁴ Department of Human Genetics, University of California Los Angeles, Los Angeles, CA, USA.
¹⁵ Bioinformatics Interdepartmental Program, University of California Los Angeles, Los Angeles, CA, USA.
¹⁶ Center for Computational Brain Research, Sudha Gopalakrishnan Brain Centre, Indian Institute of Technology Madras, Chennai, India.
¹⁷ Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA, USA.
¹⁸ Center for Brain Science, Harvard University, Cambridge, MA, USA.
¹⁹ Howard Hughes Medical Institute, Cambridge, MA, USA.
²⁰ Department of Neuroscience and Experimental Therapeutics, College of Medicine, The Pennsylvania State University, Hershey, PA, USA.
²¹ Department of Neuroscience, Yale School of Medicine, New Haven, CT, USA.
²² Molecular Neurobiology Unit, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
²³ Center for AI and Computational Biology, VIB, Leuven, Belgium.
²⁴ VIB-KU Leuven Center for Brain and Disease Research, Leuven, Belgium.
²⁵ Department of Human Genetics, KU Leuven, Leuven, Belgium.
²⁶ Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.
²⁷ Department of Anatomy, University of California San Francisco, San Francisco, CA, USA.
²⁸ Department of Psychiatry and Behavioral Sciences, University of California San Francisco, San Francisco, CA, USA.
²⁹ Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA.
³⁰ Kavli Institute for Fundamental Neuroscience, University of California San Francisco, San Francisco, CA, USA.
³¹ Physiology Department and Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada.
³² Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, USA.
³³ Department of Biomedical Engineering, Yale University, New Haven, CT, USA.
³⁴ Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA.
³⁵ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
³⁶ Princeton Neuroscience Institute, Princeton University, Princeton, NJ, USA.
³⁷ Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
³⁸ Department of Computational Medicine, University of California Los Angeles, Los Angeles, CA, USA.
³⁹ Department of Neurology, University of California Los Angeles, Los Angeles, CA, USA.
⁴⁰ Department of Biological Chemistry, University of California Los Angeles, Los Angeles, CA, USA. ABhaduri@mednet.ucla.edu.
⁴¹ Allen Institute for Brain Science, Seattle, WA, USA. HongkuiZ@alleninstitute.org.
⁴² Department of Biochemistry, University of Washington School of Medicine, Seattle, WA, USA. HongkuiZ@alleninstitute.org.

PMID: 41193845
DOI: 10.1038/s41586-025-09652-1

Review

The new frontier in understanding human and mammalian brain development

Tomasz J Nowakowski et al. Nature. 2025 Nov.

. 2025 Nov;647(8088):51-59.

doi: 10.1038/s41586-025-09652-1. Epub 2025 Nov 5.

Authors

Affiliations

¹ Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA. Tomasz.nowakowski@ucsf.edu.
² Department of Anatomy, University of California San Francisco, San Francisco, CA, USA. Tomasz.nowakowski@ucsf.edu.
³ Department of Psychiatry and Behavioral Sciences, University of California San Francisco, San Francisco, CA, USA. Tomasz.nowakowski@ucsf.edu.
⁴ The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, CA, USA. Tomasz.nowakowski@ucsf.edu.
⁵ Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA. Tomasz.nowakowski@ucsf.edu.
⁶ Kavli Institute for Fundamental Neuroscience, University of California San Francisco, San Francisco, CA, USA. Tomasz.nowakowski@ucsf.edu.
⁷ Department of Biological Chemistry, University of California Los Angeles, Los Angeles, CA, USA.
⁸ Children's Hospital Los Angeles, Los Angeles, CA, USA.
⁹ Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
¹⁰ Allen Institute for Brain Science, Seattle, WA, USA.
¹¹ The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, CA, USA.
¹² Department of Neurology, University of California San Francisco, San Francisco, CA, USA.
¹³ Genomic Analysis Laboratory, The Salk Institute for Biological Studies, La Jolla, CA, USA.
¹⁴ Department of Human Genetics, University of California Los Angeles, Los Angeles, CA, USA.
¹⁵ Bioinformatics Interdepartmental Program, University of California Los Angeles, Los Angeles, CA, USA.
¹⁶ Center for Computational Brain Research, Sudha Gopalakrishnan Brain Centre, Indian Institute of Technology Madras, Chennai, India.
¹⁷ Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA, USA.
¹⁸ Center for Brain Science, Harvard University, Cambridge, MA, USA.
¹⁹ Howard Hughes Medical Institute, Cambridge, MA, USA.
²⁰ Department of Neuroscience and Experimental Therapeutics, College of Medicine, The Pennsylvania State University, Hershey, PA, USA.
²¹ Department of Neuroscience, Yale School of Medicine, New Haven, CT, USA.
²² Molecular Neurobiology Unit, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
²³ Center for AI and Computational Biology, VIB, Leuven, Belgium.
²⁴ VIB-KU Leuven Center for Brain and Disease Research, Leuven, Belgium.
²⁵ Department of Human Genetics, KU Leuven, Leuven, Belgium.
²⁶ Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.
²⁷ Department of Anatomy, University of California San Francisco, San Francisco, CA, USA.
²⁸ Department of Psychiatry and Behavioral Sciences, University of California San Francisco, San Francisco, CA, USA.
²⁹ Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA.
³⁰ Kavli Institute for Fundamental Neuroscience, University of California San Francisco, San Francisco, CA, USA.
³¹ Physiology Department and Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada.
³² Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, USA.
³³ Department of Biomedical Engineering, Yale University, New Haven, CT, USA.
³⁴ Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA.
³⁵ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
³⁶ Princeton Neuroscience Institute, Princeton University, Princeton, NJ, USA.
³⁷ Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
³⁸ Department of Computational Medicine, University of California Los Angeles, Los Angeles, CA, USA.
³⁹ Department of Neurology, University of California Los Angeles, Los Angeles, CA, USA.
⁴⁰ Department of Biological Chemistry, University of California Los Angeles, Los Angeles, CA, USA. ABhaduri@mednet.ucla.edu.
⁴¹ Allen Institute for Brain Science, Seattle, WA, USA. HongkuiZ@alleninstitute.org.
⁴² Department of Biochemistry, University of Washington School of Medicine, Seattle, WA, USA. HongkuiZ@alleninstitute.org.

PMID: 41193845
DOI: 10.1038/s41586-025-09652-1

Abstract

Neurodevelopmental disorders that cause cognitive, behavioural or motor impairments affect around 15% of children and adolescents worldwide¹, with diagnoses of profound autism and attention deficit hyperactivity disorder increasing in the USA and contributing to a major economic burden^2,3. Yet the origins and mechanisms of these conditions remain poorly understood, limiting progress in therapies. Comprehensive cell atlases of the developing human brain, alongside those of model organisms such as mice and non-human primates, are now providing high-resolution measures of gene expression, cell-type abundance and spatial distribution. In this Perspective, we highlight recent studies that have identified novel developmental cell populations, revealed conserved and divergent patterns of cell genesis, migration and maturation across species, and begun testing hypotheses that link them to processes ranging from transcriptional control of cell fate specification to the emergence of complex behaviours. We present remaining conceptual and technical challenges and provide an outlook on how further studies of human and mammalian brain development can empower a deeper understanding of neurodevelopmental and neuropsychiatric disorders. Future efforts expanding to additional developmental stages, including adolescence, as well as whole-brain, multimodal and cross-species integration, will yield new insights into how development shapes the brain. These atlases promise to serve as essential references for unravelling mechanisms of brain function and disease vulnerability, and for advancing precision medicine.

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Conflict of interest statement

Competing interests: H.Z. is on the scientific advisory board of MapLight Therapeutics. N.S. is a co-founder and board member of Bexorg. A.R.K. is a co-founder of and consultant to Neurona Therapeutics.

References

1. Gidziela, A. et al. A meta-analysis of genetic effects associated with neurodevelopmental disorders and co-occurring conditions. Nat. Hum. Behav. 7, 642–656 (2023). - PubMed - PMC
1. Buescher, A. V. S., Cidav, Z., Knapp, M. & Mandell, D. S. Costs of autism spectrum disorders in the United Kingdom and the United States. JAMA Pediatr. 168, 721–728 (2014). - PubMed
1. Leigh, J. P. & Du, J. Brief report: Forecasting the economic burden of autism in 2015 and 2025 in the United States. J. Autism Dev. Disord. 45, 4135–4139 (2015). - PubMed
1. Molnár, Z. et al. New insights into the development of the human cerebral cortex. J. Anat. 235, 432–451 (2019). - PubMed - PMC
1. Wallace, J. L. & Pollen, A. A. Human neuronal maturation comes of age: cellular mechanisms and species differences. Nat. Rev. Neurosci. 25, 7–29 (2024). - PubMed

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The new frontier in understanding human and mammalian brain development

Affiliations

The new frontier in understanding human and mammalian brain development

Authors

Affiliations

Abstract

Conflict of interest statement

References

Publication types

MeSH terms

LinkOut - more resources

Full Text Sources