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人类大脑类器官中 和 的功能差异揭示了早期皮质发生中受体特异性作用。

Functional Divergence of and in Human Cerebral Organoids Reveals Receptor-Specific Roles in Early Corticogenesis.

作者信息

Yakovleva Sophia, Knyazeva Anastasia, Yunusova Anastasia, Allayarova Elina, Lanshakov Dmitriy, Malashicheva Anna, Shnaider Tatiana

机构信息

Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, 630090 Novosibirsk, Russia.

Department of Natural Sciences, V. Zelman Institute for Medicine and Psychology, Novosibirsk State University, 630090 Novosibirsk, Russia.

出版信息

Int J Mol Sci. 2025 Jul 29;26(15):7309. doi: 10.3390/ijms26157309.


DOI:10.3390/ijms26157309
PMID:40806441
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12347189/
Abstract

The Notch signaling pathway is a critical regulator of embryonic brain development. Among its four mammalian receptors, Notch1 and Notch2 are particularly significant in the developing cortex, yet their roles in human neurodevelopment are not well understood. In murine cortex development, primarily regulates early progenitor identity and neurogenesis, while is required for maintaining radial glial cells at later stages. However, it is unclear whether these functions are conserved in the human developing brain. In this study, we used cerebral organoids as an in vitro model of early human corticogenesis and conducted lentiviral shRNA-mediated knockdowns of and . Our findings indicate that is essential for organoid growth, lumen morphogenesis, radial glial identity, and progenitor proliferation. In contrast, depleting did not significantly affect these early developmental processes. These results demonstrate that and have potentially non-redundant and temporally distinct roles in early human corticogenesis, reflecting receptor-specific specialization within the Notch signaling pathway.

摘要

Notch信号通路是胚胎脑发育的关键调节因子。在其四种哺乳动物受体中,Notch1和Notch2在发育中的皮层中尤为重要,但其在人类神经发育中的作用尚未得到充分了解。在小鼠皮层发育中,主要调节早期祖细胞的特性和神经发生,而在后期维持放射状胶质细胞则需要 。然而,尚不清楚这些功能在人类发育中的大脑中是否保守。在本研究中,我们使用脑类器官作为早期人类皮质发生的体外模型,并通过慢病毒shRNA介导对 和 进行敲低。我们的研究结果表明, 对于类器官生长、管腔形态发生、放射状胶质细胞特性和祖细胞增殖至关重要。相比之下,耗尽 并没有显著影响这些早期发育过程。这些结果表明, 和 在早期人类皮质发生中具有潜在的非冗余和时间上不同的作用,反映了Notch信号通路中受体特异性的特化。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4142/12347189/91a2a9401d4d/ijms-26-07309-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4142/12347189/6ba6be7bdbfc/ijms-26-07309-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4142/12347189/b545caa69127/ijms-26-07309-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4142/12347189/0ad6d551d5c5/ijms-26-07309-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4142/12347189/91a2a9401d4d/ijms-26-07309-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4142/12347189/6ba6be7bdbfc/ijms-26-07309-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4142/12347189/b545caa69127/ijms-26-07309-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4142/12347189/0ad6d551d5c5/ijms-26-07309-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4142/12347189/91a2a9401d4d/ijms-26-07309-g004.jpg

相似文献

[1]
Functional Divergence of and in Human Cerebral Organoids Reveals Receptor-Specific Roles in Early Corticogenesis.

Int J Mol Sci. 2025-7-29

[2]
The Notch ligand Jagged1 plays a dual role in cochlear hair cell regeneration.

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[3]
Chronic haloperidol exposure impairs neurodevelopment via Notch1 signaling in human stem cell-derived brain organoids.

Sci Rep. 2025-7-17

[4]
NOTCH1 and NOTCH2 regulate epithelial cell proliferation in mouse and human gastric corpus.

Am J Physiol Gastrointest Liver Physiol. 2017-2-1

[5]
A human-specific enhancer fine-tunes radial glia potency and corticogenesis.

Nature. 2025-5-14

[6]
Diversity in Notch ligand-receptor signaling interactions.

Elife. 2025-1-3

[7]
Prescription of Controlled Substances: Benefits and Risks

2025-1

[8]
Notch1 and Notch2 receptors regulate mouse and human gastric antral epithelial cell homoeostasis.

Gut. 2017-6

[9]
Upregulated NOTCH2 Expression Is Implicated in the Clinical Aggressiveness of Atypical Fibroxanthoma and Pleomorphic Dermal Sarcoma.

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[10]
The glycosyltransferase POGLUT1 regulates muscle stem cell development and maintenance in mice.

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本文引用的文献

[1]
A dyad of human-specific and orchestrates cortical progenitor abundance crucial for human neocortex expansion.

Sci Adv. 2025-3-28

[2]
Endothelial-mesenchymal crosstalk drives osteogenic differentiation of human osteoblasts through Notch signaling.

Cell Commun Signal. 2025-2-19

[3]
Diversity in Notch ligand-receptor signaling interactions.

Elife. 2025-1-3

[4]
Tissue morphology influences the temporal program of human brain organoid development.

Cell Stem Cell. 2023-10-5

[5]
Notch1 cortical signaling regulates epithelial architecture and cell-cell adhesion.

J Cell Biol. 2023-12-4

[6]
Notch directs telencephalic development and controls neocortical neuron fate determination by regulating microRNA levels.

Development. 2023-6-1

[7]
Roles of the Notch signaling pathway and microglia in autism.

Behav Brain Res. 2023-2-2

[8]
Asymmetric Notch activity by differential inheritance of lysosomes in human neural stem cells.

Sci Adv. 2022-2-11

[9]
Notch1 and Notch2 collaboratively maintain radial glial cells in mouse neurogenesis.

Neurosci Res. 2021-9

[10]
Canonical Notch ligands and Fringes have distinct effects on NOTCH1 and NOTCH2.

J Biol Chem. 2020-10-23

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