Early indirect neurogenesis transitions to late direct neurogenesis in mouse cerebral cortex development

Cárdenas A, Çelik I, Espinós A, Streicher C, López-González L, del-Valle-Anton L, Fernández V, Amin S, Negri E, Ortuño EF, Hippenmeyer S, Borrell V. Early indirect neurogenesis transitions to late direct neurogenesis in mouse cerebral cortex development. bioRxiv, 10.1101/2025.05.22.655488.

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Author
Cárdenas, Adrián; Çelik, Irem; Espinós, Alexandre; Streicher, CarmenISTA; López-González, Lara; del-Valle-Anton, Lucia; Fernández, Virginia; Amin, Salma; Negri, Enrico; Ortuño, Eduardo Fernández; Hippenmeyer, SimonISTA ; Borrell, Víctor
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Abstract
The cerebral cortex must contain the appropriate numbers of neurons in each layer to acquire its proper functional organization. Accordingly, neurogenesis requires precise regulation along development. Cortical neurons are made either directly by Radial Glia Cells (RGCs) that self- consume, or indirectly from RGCs via Intermediate Progenitor Cells (IPCs) and largely preserving the RGC pool. According to the standing model of cortical development, Direct Neurogenesis predominates at early stages of development, and progressively shifts to Indirect Neurogenesis, which predominates at late stages. However, neurogenesis at early stages should be compatible with RGC amplification, and neurogenesis at late stages needs to involve RGC consumption, which seems in conflict with the standing model. Here we studied the modes of neurogenesis along cortical development using multiple approaches, including birthdating, live imaging and MADM clone labeling. Contrary to the established dogma, our data show that Indirect Neurogenesis clearly predominates at early developmental stages, gradually shifting to Direct Neurogenesis at late stages. These findings challenge the current model of cortical neurogenesis, and prompt a re-evaluation of previous and ongoing work about the genetic and molecular mechanisms regulating this process.
Publishing Year
Date Published
2025-05-23
Journal Title
bioRxiv
Acknowledgement
We thank A. Iñigo for assistance with imaging, and members of the Borrell and Herrera labs for insightful discussions and critical reading of the manuscript. Funding to our lab members was provided by the Spanish Research Agency (AEI): FPI contract (BES-2016-077737) to L.dV.A., FPI SO contract (SEV-2017-0723-18-1) to A.E., JdC-Incorporación contract (IJC2020-044653-I) to V.F., and JAE-Intro fellowship (JAEICU23EX_0071) to I.C., as well as by La Caixa Foundation: La Caixa-Severo Ochoa fellowship (E-03-2016-0557140) to S.A., INPhINIT-Retaining fellowship (LCF/BQ/DR21/11880012) to E.F.O., INPhINIT-Incoming fellowship (LCF/BQ/DI22/11940006) to E.N., and Junior Leader-Retaining grant to A.C. (LCF/BQ/PR23/11980051). Work was supported by grants from FWF (SFB F78) to S.H.; AEI (PID2021-125618NB-I00) and European Research Council (101118729) to V.B., who also acknowledges financial support from AEI through the “Severo Ochoa” Programme for Centers of Excellence in R&D (CEX2021-001165-S).
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Cárdenas A, Çelik I, Espinós A, et al. Early indirect neurogenesis transitions to late direct neurogenesis in mouse cerebral cortex development. bioRxiv. doi:10.1101/2025.05.22.655488
Cárdenas, A., Çelik, I., Espinós, A., Streicher, C., López-González, L., del-Valle-Anton, L., … Borrell, V. (n.d.). Early indirect neurogenesis transitions to late direct neurogenesis in mouse cerebral cortex development. bioRxiv. https://doi.org/10.1101/2025.05.22.655488
Cárdenas, Adrián, Irem Çelik, Alexandre Espinós, Carmen Streicher, Lara López-González, Lucia del-Valle-Anton, Virginia Fernández, et al. “Early Indirect Neurogenesis Transitions to Late Direct Neurogenesis in Mouse Cerebral Cortex Development.” BioRxiv, n.d. https://doi.org/10.1101/2025.05.22.655488.
A. Cárdenas et al., “Early indirect neurogenesis transitions to late direct neurogenesis in mouse cerebral cortex development,” bioRxiv. .
Cárdenas A, Çelik I, Espinós A, Streicher C, López-González L, del-Valle-Anton L, Fernández V, Amin S, Negri E, Ortuño EF, Hippenmeyer S, Borrell V. Early indirect neurogenesis transitions to late direct neurogenesis in mouse cerebral cortex development. bioRxiv, 10.1101/2025.05.22.655488.
Cárdenas, Adrián, et al. “Early Indirect Neurogenesis Transitions to Late Direct Neurogenesis in Mouse Cerebral Cortex Development.” BioRxiv, doi:10.1101/2025.05.22.655488.
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