Transcriptional dynamics orchestrating the development and integration of neurons born in the adult hippocampus.

SOXC Transcription Factors; Sox4 protein, mouse; Sox11 protein, mouse; Transcription Factors; Mice; Transcription, Genetic; Gene Expression Profiling; Transcription Factors/genetics; Neurons/cytology; SOXC Transcription Factors/metabolism; SOXC Transcription Factors/genetics; Cell Differentiation/genetics; Neurogenesis/genetics; Cellular state; Differential gene expressions; Early differentiation; Effector genes; Functional capabilities; Granule cells; Molecular mechanism; Synaptogenesis; Time trajectories; Transcriptional profiling; Cell Differentiation; Hippocampus; Neurogenesis; Neurons

Abstract :

[en] The adult hippocampus generates new granule cells (aGCs) with functional capabilities that convey unique forms of plasticity to the preexisting circuits. While early differentiation of adult radial glia-like cells (RGLs) has been studied extensively, the molecular mechanisms guiding the maturation of postmitotic neurons remain unknown. Here, we used a precise birthdating strategy to study aGC differentiation using single-nuclei RNA sequencing. Transcriptional profiling revealed a continuous trajectory from RGLs to mature aGCs, with multiple immature stages bearing increasing levels of effector genes supporting growth, excitability, and synaptogenesis. Analysis of differential gene expression, pseudo-time trajectory, and transcription factors (TFs) revealed critical transitions defining four cellular states: quiescent RGLs, proliferative progenitors, immature aGCs, and mature aGCs. Becoming mature aGCs involved a transcriptional switch that shuts down pathways promoting cell growth, such SoxC TFs, to activate programs that likely control neuronal homeostasis. aGCs overexpressing Sox4 or Sox11 remained immature. Our results unveil precise molecular mechanisms driving adult RGLs through the pathway of neuronal differentiation.

Disciplines :

Biochemistry, biophysics & molecular biology
Life sciences: Multidisciplinary, general & others

Author, co-author :

Rasetto, Natali Belen ^✱; Université de Liège - ULiège > Département des sciences biomédicales et précliniques ; Instituto de Investigaciones Biomédicas de Buenos Aires (IIBBA) - CONICET, Buenos Aires, Argentina ; Laboratory of Neuronal Plasticity, Leloir Institute, Buenos Aires, Argentina

Giacomini, Damiana ^✱; Instituto de Investigaciones Biomédicas de Buenos Aires (IIBBA) - CONICET, Buenos Aires, Argentina ; Laboratory of Neuronal Plasticity, Leloir Institute, Buenos Aires, Argentina

Berardino, Ariel A ^✱; Instituto de Investigaciones Biomédicas de Buenos Aires (IIBBA) - CONICET, Buenos Aires, Argentina ; Laboratory of Integrative Systems Biology, Leloir Institute, Buenos Aires, Argentina

Waichman, Tomás Vega ; Instituto de Investigaciones Biomédicas de Buenos Aires (IIBBA) - CONICET, Buenos Aires, Argentina ; Laboratory of Integrative Systems Biology, Leloir Institute, Buenos Aires, Argentina

Beckel, Maximiliano S ; Instituto de Investigaciones Biomédicas de Buenos Aires (IIBBA) - CONICET, Buenos Aires, Argentina ; Laboratory of Integrative Systems Biology, Leloir Institute, Buenos Aires, Argentina

Di Bella, Daniela J ; Department of Stem Cells and Regenerative Biology, Harvard University and Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA

Brown, Juliana ; Department of Stem Cells and Regenerative Biology, Harvard University and Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA

Davies-Sala, M Georgina ; Instituto de Investigaciones Biomédicas de Buenos Aires (IIBBA) - CONICET, Buenos Aires, Argentina ; Laboratory of Neuronal Plasticity, Leloir Institute, Buenos Aires, Argentina

Gerhardinger, Chiara ; Department of Stem Cells and Regenerative Biology, Harvard University and Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA

Lie, Dieter Chichung ; Institute of Biochemistry, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany

More authors (3 more)

^✱ These authors have contributed equally to this work.

Language :

English

Title :

Transcriptional dynamics orchestrating the development and integration of neurons born in the adult hippocampus.

Publication date :

19 July 2024

Journal title :

Science Advances

eISSN :

2375-2548

Publisher :

American Association for the Advancement of Science, United States

Volume :

Issue :

Pages :

eadp6039

Peer reviewed :

Peer Reviewed verified by ORBi

Additional URL :

https://www.science.org/doi/pdf/10.1126/sciadv.adp6039

Funding text :

We thank members of the A.F.S., A.C., G. Lanuza, and E. Kropff labs for insightful discussions and M. Trinchero for critical comments on the manuscript. D.G., A.C., and A.F.S. are investigators in the Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICE T). N.B.R., A.A.B., and M.S.B. were supported by CONICE T fellowships. P.A. is a SAB member at Foresite Labs, CNSII, and is a cofounder and a SAB member of Vesalius Therapeutics. Funding: This work was supported by NIH grants from the National Institute of Neurological Disorders and Stroke (NINDS), R01NS128117 (P.A.); NINDS and Fogarty International Center, R01NS103758 (A.F.S. and P.A.); and the Argentine Agency for the Promotion of Science and Technology, PICT 2017-0389 (D.G.), PICT 2018-03713 (A.C.), and PICT-2020- 0046 and PICT-2021- 0077 (A.F.S.). Author contributions: Conceptualization: N.B.R., D.G., A.A.B., P.A., A.C., and A.F.S. Software: A.A.B., T.V.W., M.S.B., and A.C. Investigation: N.B.R., D.G., D.J.B.D., J.B., M.G.D.-S., and C.G. Resources: D.C.L. Data curation: A.A.B., T.V.W., M.S.B., and A.C. Visualization: N.B.R., D.G., A.A.B., T.V.W., M.S.B., A.C., and A.F.S. Supervision: P.A., A.C., and A.F.S. Writing-original draft: N.B.R., D.G., A.A.B., M.S.B., A.C., and A.F.S. Writing-review and editing: T.V.W., D.J.D.B., D.C.L., and P.A. Competing interests: P.A. is a SAB member at Foresite Labs, CNSII, and is a cofounder and a SAB member of Vesalius Therapeutics. The authors declare that they have no other competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Datasets 1 and 2 have been deposited in the Gene Expression Omnibus site (accession GSE249796). The computational scripts used in our analysis are available in the Zenodo repository (doi: 10.5281/zenodo.11371903).Acknowledgments: We thank members of the A.F.S., A.c., G. Lanuza, and e. Kropff labs for insightful discussions and M. Trinchero for critical comments on the manuscript. d.G., A.c., and A.F.S. are investigators in the consejo nacional de investigaciones cientificas y Tecnicas (coniceT). n.B.R., A.A.B., and M.S.B. were supported by coniceT fellowships. P.A. is a SAB member at Foresite Labs, cnSii, and is a cofounder and a SAB member of vesalius Therapeutics. Funding: This work was supported by nih grants from the national institute of neurological disorders and Stroke (nindS), R01nS128117 (P.A.); nindS and Fogarty international center, R01nS103758 (A.F.S. and P.A.); and the Argentine Agency for the Promotion of Science and Technology, PicT 2017-0389 (d.G.), PicT 2018-03713 (A.c.), and PicT-2020-0046 and PicT-2021-0077 (A.F.S.). Author contributions: conceptualization: n.B.R., d.G., A.A.B., P.A., A.c., and A.F.S. Software: A.A.B., T.v.W., M.S.B., and A.c. investigation: n.B.R., d.G., d.J.B.d., J.B., M.G.d.-S., and c.G. Resources: d.c.L. data curation: A.A.B., T.v.W., M.S.B., and A.c. visualization: n.B.R., d.G., A.A.B., T.v.W., M.S.B., A.c., and A.F.S. Supervision: P.A., A.c., and A.F.S. Writing\u2014original draft: n.B.R., d.G., A.A.B., M.S.B., A.c., and A.F.S. Writing\u2014review and editing: T.v.W., d.J.d.B., d.c.L., and P.A. Competing interests: P.A. is a SAB member at Foresite Labs, cnSii, and is a cofounder and a SAB member of vesalius Therapeutics. The authors declare that they have no other competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. datasets 1 and 2 have been deposited in the Gene expression omnibus site (accession GSe249796). The computational scripts used in our analysis are available in the Zenodo repository (doi: 10.5281/zenodo.11371903).

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