TempShift Reveals the Sequential Development of Human Neocortex and Skewed Developmental Timing of Down Syndrome Brains
Open accessAbstract
Development is a complex process involving precise regulation. Developmental regulation may vary in tissues and individuals, and is often altered in disorders. Currently, the regulation of developmental timing across neocortical areas and developmental changes in Down syndrome (DS) brains remain unclear. The changes in regulation are often accompanied by changes in the gene expression trajectories, which can be divided into two scenarios: (1) changes of gene expression trajectory shape that reflect changes in cell type composition or altered molecular machinery; (2) temporal shift of gene expression trajectories that indicate different regulation of developmental timing. Therefore, we developed an R package TempShift to separates these two scenarios and demonstrated that TempShift can distinguish temporal shift from different shape (DiffShape) of expression trajectories, and can accurately estimate the time difference between multiple trajectories. We applied TempShift to identify sequential gene expression across 11 neocortical areas, which suggested sequential occurrence of synapse formation and axon guidance, as well as reconstructed interneuron migration pathways within neocortex. Comparison between healthy and DS brains revealed increased microglia, shortened neuronal migration process, and delayed synaptogenesis and myelination in DS. These applications also demonstrate the potential of TempShift in understanding gene expression temporal dynamics during different biological processes.
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Studies using transcriptomics and new analytical tools have suggested that neurogenesis, gliogenesis and myelination may be temporally altered in Down syndrome.
“Indeed, studies using transcriptomics and new analytical tools have suggested that neurogenesis, gliogenesis and myelination may be temporally altered in DS39,106,107.”
From Consequences of trisomy 21 for brain development in Down syndrome (2024) · cites this paper as [106]
Results §3.5 reports delayed expression of oligodendrocyte-enriched genes, including myelin basic protein, and says other shifted genes imply delayed oligodendrocyte generation in Down syndrome. This supports possible timing changes related to gliogenesis and myelination. The Introduction mentions defects in neurogenesis, but the cited results do not establish a temporal alteration in neurogenesis; neuronal migration is a distinct process. Page numbers were not available in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredDown syndrome cortical development shows a temporal shift of gene expression trajectories.
“The authors have used TempShift — an R-based algorithm — to reveal a temporal shift of gene expression trajectories in Down syndrome cortical development.”
From Consequences of trisomy 21 for brain development in Down syndrome (2024) · cites this paper as [106]
TempShift revealed several genes displaying heterochronic expression in DS, including several synaptic proteins.
“Furthermore, a recent study has applied a new algorithm, TempShift, that detects heterochronic expression of genes between species or between individuals with a disease and matched controls, and revealed several genes displaying heterochronic expression in DS, including several synaptic proteins106,152.”
From Consequences of trisomy 21 for brain development in Down syndrome (2024) · cites this paper as [106]
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- Authors
- Zhou, Y., Tao, L., & Zhu, Y.
- Affiliations
- Fudan University (CN)
- Corresponding author
- Zhu, Ying
- Venue
- Brain Sciences
- Publisher
- MDPI AG
- Published
- 2023-07-13
- Volume
- 13
- Issue
- 7
- Pages
- 1070
- ISSN
- 2076-3425 (ISSN-L)
- PMC
- PMC10377154
- OpenAlex
- W4384340537
- Cited by
- 7
- References
- 28
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 2 · 2022: 1
- FWCI
- 0.53
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Brain Sciences (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Shanghai Municipal Science and Technology Major Project (2018SHZDZX01, 021ZD0200100, 82071259)
- STI2030-Major Projects (2018SHZDZX01, 021ZD0200100, 82071259)
- National Natural Science Foundation of China (2018SHZDZX01, 021ZD0200100, 82071259)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
- Keywords
- gene expression trajectories, developmental timing, neocortex development, Down syndrome, temporal shifts, trajectory shape, synaptogenesis, axon guidance, interneuron migration, microglia, neuronal migration, myelination, R package
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