Histone crotonylation/acetylation regulates cell non-autonomously cortical interneuron development

• Applicant: Professorin Dr. Tanja Vogel
• Subject Area: Developmental Neurobiology
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 577348470

The developing brain relies on a concerted and orchestrated program of diverse gene activities in order to build the neural networks necessary for proper brain functions. In this context the balance between excitatory (E) and inhibitory (I) neurons needs to be tightly controlled. This notion is underlined by the finding that disbalanced E/I activities are associated with neurological and psychiatric diseases. The proposed project aims to study how the balance between the two populations is realized during mouse cerebral cortex development. The project is following up on our analysis of a mouse mutant, in which Af9/Mllt3 was deleted specifically in basal progenitors (BPs) of the glutamatergic lineage using Eomes-cre. Preliminary data from single-cell RNA-sequencing analysis of the dorsal telencephalon of mutant and control animals showed that specifically the interneuron population originating from the caudal ganglionic eminences appeared in altered numbers in the mutant cerebral cortex. Our prevailing hypothesis is that the loss of MLLT3 function in the BP lineage changes specifically signaling pathways that impact invading interneurons. This view is supported by preliminary bioinformatics prediction. Within the proposed we aim to specify the signaling pathways that originate from cells of the glutamatergic lineage in the cerebral cortex, which influence the invading interneurons, and to determine the underlying epigenetic changes that are associated with misexpression of MLLT3. Specifically, we will (i) extend existing single-cell RNA-sequencing data sets (from the timepoints E14.5 and E16.5) to three later timepoints (E18.5, P0, P21) to unravel a putative developmental dynamics in the appearance of interneurons in mutant vs. control forebrains. (ii) We will perform bioinformatics predictions, based on the single-cell RNA-sequencing data, of signaling pathways that have an origin in BPs and impact invading interneurons at all timepoints. (iii) We will study the underlying mechanism(s) that lead to altered signaling from the excitatory to the inhibitory cell lineage. In this regard we will study histone H3 lysine 9 crotonylation and H3 lysine 27 acetylation as modifications that are bound by Mllt3 and which are potentially altered through interaction of MLLT3 with HDAC1/2. This study is based on single-cell CUT&TAG analysis in support of single-cell ATAC to resolve altered accessibility of the chromatin in response to altered crotonylation/acetylation. (iv) We will validate and characterize the signaling pathways with altered activity upon Mllt3 deficiency that orchestrate the intricate balance between the excitatory and the inhibitory lineages. Taken together, this project will give novel insights into epigenetic changes in progenitors and neurons of the excitatory lineage, that impact on specific signaling molecules and pathways that are functionally involved to regulate the appearance of interneuron numbers during cortical development.

• DFG Programme: Research Grants