A dynamic gene regulatory code drives synaptic development of hippocampal granule cells
Connecting neurons into functional circuits requires the formation, maturation, and plasticity of synapses. While advances have been made in identifying individual genes regulating synapse development, the molecular programs orchestrating their action during circuit integration of neurons remain poorly understood. Here, we take a multiomic approach to reconstruct gene regulatory networks (GRNs), comprising transcription factors (TFs), regulatory regions, and predicted target genes, in hippocampal granule cells (GCs). We find a dynamic gene regulatory code, with early and late postnatal GRNs regulating cell morphogenesis and synapse organization and plasticity, respectively. Our results predict sequential regulations, with early-active TFs delaying the activation of later GRNs and their putative synaptic targets. Using a loss-of-function approach, we identify <i>Bcl6</i> as a regulator of pre- and postsynaptic structural maturation and synaptic transmission and <i>Smad3</i> as a modulator of inhibitory synaptic transmission in GCs. Together, these findings highlight the networks of key TFs and target genes orchestrating GC synapse development.
Authors
- Stein Aerts (ORCID: https://orcid.org/0000-0002-8006-0315)
- Kristofer Davie (ORCID: https://orcid.org/0000-0003-2182-1249)
- Danie Daaboul (ORCID: https://orcid.org/0000-0001-8542-650X)
- Ine Vlaeminck (ORCID: https://orcid.org/0000-0001-8934-6179)
- Joris Vandenbempt (ORCID: https://orcid.org/0009-0004-9012-4775)
- Joris de Wit (ORCID: https://orcid.org/0000-0003-1120-1089)
- Gabriele Marcassa (ORCID: https://orcid.org/0000-0001-8848-2136)
- Dan Dascenco (ORCID: https://orcid.org/0000-0002-4629-8266)
- Suresh Poovathingal (ORCID: https://orcid.org/0000-0002-3236-2255)
- Jan Lamote (ORCID: https://orcid.org/0000-0003-1862-958X)
- Keimpe Wierda (ORCID: https://orcid.org/0000-0002-8784-9490)
- Blanca Lorente-Echeverría (ORCID: https://orcid.org/0000-0003-4739-0926)
- Elke Leysen (ORCID: https://orcid.org/0000-0002-5606-6725)
- Jeroen Vandensteen (ORCID: https://orcid.org/0009-0004-5084-7696)
- Lise Vervloessem
- Willem Naert (ORCID: https://orcid.org/0009-0005-4925-3281)
- Malou Reverendo
Institutions
- VIB-KU Leuven Center for Cancer Biology (BE)
- VIB-KU Leuven Center for Microbiology (BE)
- VIB-KU Leuven Center for Brain & Disease Research (BE)
- KU Leuven (BE)
Publication Details
- Journal
- Science Advances
- Published
- 2025-10-22
- DOI
- https://doi.org/10.1126/sciadv.adx5140
- Primary Topic
- Single-cell and spatial transcriptomics
- Type
- article
- Field-Weighted Citation Impact
- 0.00