Christian MayerNew preprint: "Stoichiometric transcription factor partnerships control GABAergic neuron fate allocation."
Cell identity in development is often described as a combinatorial transcription factor "code." We find it is also quantitative: not only which factors are present, but their relative abundance, can shape a cell's fate.
In the developing basal ganglia, a pool of undifferentiated progenitors gives rise to several GABAergic neuron types, including D1 and D2 medium spiny neurons. Using our in vivo clonal perturbation sequencing and clone2vec, we find that losing SP9 shifts the clonal fate bias of progenitors from D2 neurons toward other GABAergic fates.
The readout uses two modes of genome binding: at GC-rich promoters SP9 binds DNA directly and activates; at distal enhancers it binds indirectly, tethered by DLX, acting as a combinatorial repressor with the NuRD complex. When DLX is in excess it sequesters SP9 away from its activating targets, so a graded shift in the SP9:DLX ratio becomes a discrete fate choice. An SP9 variant linked to neurodevelopmental disorders impairs the activator mode.
With thanks to the team, collaborators, and to #SFARI, the #DFG and the #NLMFF.
Stoichiometric transcription factor partnerships control GABAergic neuron fate allocation
Combinatorial transcription factor (TF) codes specify neuronal fates, yet how quantitative differences in interacting TFs shape these decisions remains unresolved. We address this in the developing basal ganglia, where a pool of undifferentiated progenitors gives rise to both D1 and D2 medium spiny neurons (MSNs). Combining sparse in vivo CRISPR perturbation, lineage barcoding, and single-cell transcriptomics in mice, we find that loss of Sp9 shifts clonal fate bias from D2 toward D1 MSNs and intercalated cells. Mechanistically, chromatin profiling and biochemical assays show that at GC-rich promoters, SP9 binds DNA directly and activates transcription. At distal enhancers, SP9 binds indirectly, tethered by DLX factors, represses activity, and associates with the NuRD corepressor complex. The relative abundance of SP9 and DLX selects between these modes. These findings extend the combinatorial TF code beyond factor identity to relative proportions, with relevance to neurodevelopmental disorders. ### Competing Interest Statement The authors have declared no competing interest. Deutsche Forschungsgemeinschaft, https://ror.org/018mejw64, 549328218 Simons Foundation, https://ror.org/01cmst727, SFI-AN-AR-Pilot-00009814 Nancy Lurie Marks Family Foundation European Molecular Biology Organization, https://ror.org/04wfr2810, EMBO Young Investigator Programme
