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CRL4<sup>AMBRA1</sup> is a key mediator for AKT-dependent cell cycle control in neural progenitor cells.

Overview

Authors: He Wang1,2, Panmiao Liu1, Runmin Wang2, Hanwen Gu1, Tingting Zhu1, Guiquan Chen2, Jian-Jun Yang1,3
ORCID iDs: He Wang, Hanwen Gu, Guiquan Chen, Jian-Jun Yang
  1. Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
  2. MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Medical School, Nanjing University, Nanjing, China
  3. Department of Anesthesiology and Perioperative Medicine, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
Institutions: Zhengzhou University (China); Model Animal Research Center (China); First Affiliated Hospital of Zhengzhou University (China); Nanjing University (China); Jiangsu Province Hospital (China); Nanjing Medical University (China)
Journal: EMBO reports, volume 27, issue 11, pages 3099-3119
Dates: received 1 September 2025; accepted 26 March 2026; published online 27 April 2026; in print June 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1038/s44319-026-00768-7 · PMID 42045444 · PMCID PMC13260899 · OpenAlex W7156026967
Open access: gold, a free copy (OpenAlex)
Status: data only
Categories: mouse (organism)
Methods: Statistics, Evoked potentials, fMRI & imaging, Preprocessing
Keywords: Cell Cycle, Neuroscience, Post-translational Modifications & Proteolysis
MeSH: Cell Cycle Checkpoints*, DNA-Binding Proteins*, Neural Stem Cells*, Proto-Oncogene Proteins c-akt*, Ubiquitin-Protein Ligases*, Animals, Cell Cycle, Cell Proliferation, Cyclin D2, Mice, Phosphorylation (* major topic)
Topic: Neurogenesis and neuroplasticity mechanisms (Developmental Neuroscience, Neuroscience), according to OpenAlex
Funding: National Natural Science Foundation of China (32270871, 82201330, U23A20421); The First Affiliated Hospital of Zhengzhou University (ZYCXTD2023012)
Citations: not cited yet (Europe PMC); 72 references in the paper
Research resources: Mouse monoclonal anti-SOX2 RRID:AB_10842165, RRID:AB_10956166, RRID:AB_10956588, Rat monoclonal anti-CTIP2 RRID:AB_2064130, Rabbit monoclonal anti-Cyclin D2 RRID:AB_2070685, Rabbit monoclonal anti-TBR1 RRID:AB_2200219, Cy3-Donkey anti-Goat IgG (H + L) RRID:AB_2307351, RRID:AB_2315049, RRID:AB_2338046, RRID:AB_2338404, Cy3-Goat anti-Mouse IgG (H + L) RRID:AB_2338692, RRID:AB_2340846, Rabbit polyclonal anti-PAX6 RRID:AB_2565003, Mouse monoclonal anti-β-actin RRID:AB_2665433, Rabbit polyclonal anti-DDB1 RRID:AB_2764716, Mouse monoclonal anti-GAPDH RRID:AB_2801390, Mouse monoclonal anti-β-Tubulin RRID:AB_2814800, Rabbit monoclonal anti-CyclinD1 RRID:AB_2862530, Mouse monoclonal anti-HA tag RRID:AB_2881490, Mouse monoclonal anti-DYKDDDDK tag RRID:AB_2918475, Rat monoclonal anti-BrdU RRID:AB_305426, Rabbit polyclonal anti-HA tag RRID:AB_307019, RRID:AB_330302, RRID:AB_331748, Rabbit polyclonal anti-Ki67 RRID:AB_443209, RRID:AB_621842, RRID:AB_621843, Rabbit polyclonal anti-TBR2 RRID:AB_778267, Rabbit monoclonal anti-pan-AKT RRID:AB_915783

Abstract

Neural progenitor cell (NPC) proliferation is fundamental for population expansion and brain development. G1 phase control determines the cell cycle duration of NPCs and thereby affects their proliferation efficiency. However, the molecular mechanisms governing G1 phase progression in NPCs remain unclear. Here, we show that AKT gain-of-function mutations and pharmacological inhibition exert opposing effects on NPC proliferation. Consistently, Emx1-Cre-mediated deletion of Akt1/2/3 in mice impairs NPC proliferation and disrupts cortical development. We find that AKT deficiency induces G1 phase arrest and prolongs the cell cycle of NPCs. Mechanistically, we demonstrate that AKT-mediated phosphorylation inhibits the activity of CRL4AMBRA1 E3 ubiquitin ligase to safeguard cyclin D2 (CCND2) stability. Specifically, AKT phosphorylates DDB1, the adaptor of CRL4AMBRA1, which disrupts its interaction with CCND2 and reduces its degradation. These findings reveal a post-translational mechanism impacting NPC cell cycle and cortical morphogenesis, providing insight into the etiology of malformations of cortical development.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

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Data availability

The RNA-seq raw data reported in this study have been deposited in Sequence Read Achive (SRA) of NCBI under the accession number PRJNA1020756 (https://www.ncbi.nlm.nih.gov/bioproject/PRJNA1020756).

The source data of this paper are collected in the following database record: biostudies:S-SCDT-10_1038-S44319-026-00768-7 (https://www.ebi.ac.uk/biostudies/sourcedata/studies/S-SCDT-10_1038-S44319-026-00768-7).

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 30 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 7 authors, 3 keywords, 11 MeSH terms, 2 funders, 71 references, 29 RRIDs.

Cite

This paper

Wang, H., Liu, P., Wang, R., Gu, H., Zhu, T., Chen, G., & Yang, J.-J. (2026). CRL4<sup>AMBRA1</sup> is a key mediator for AKT-dependent cell cycle control in neural progenitor cells. EMBO reports, 27(11), 3099-3119. https://doi.org/10.1038/s44319-026-00768-7

BibTeX

@article{wang2026crl4,
author = {Wang, He and Liu, Panmiao and Wang, Runmin and Gu, Hanwen and Zhu, Tingting and Chen, Guiquan and Yang, Jian-Jun},
title = {{CRL4\<sup\>AMBRA1\</sup\> is a key mediator for AKT-dependent cell cycle control in neural progenitor cells}},
journal = {EMBO reports},
year = {2026},
month = apr,
volume = {27},
number = {11},
pages = {3099--3119},
publisher = {Nature Publishing Group},
issn = {1469-221X},
doi = {10.1038/s44319-026-00768-7},
url = {https://doi.org/10.1038/s44319-026-00768-7},
pmid = {42045444},
pmcid = {PMC13260899}
}

RIS

TY - JOUR
AU - Wang, He
AU - Liu, Panmiao
AU - Wang, Runmin
AU - Gu, Hanwen
AU - Zhu, Tingting
AU - Chen, Guiquan
AU - Yang, Jian-Jun
TI - CRL4<sup>AMBRA1</sup> is a key mediator for AKT-dependent cell cycle control in neural progenitor cells
T2 - EMBO reports
J2 - EMBO Rep
PY - 2026
DA - 2026/04/27
VL - 27
IS - 11
SP - 3099
EP - 3119
SN - 1469-221X
PB - Nature Publishing Group
DO - 10.1038/s44319-026-00768-7
UR - https://doi.org/10.1038/s44319-026-00768-7
LA - en
ER -

CSL-JSON

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