Biology subjects

Daaboul, D.

Publications and source records attributed to Daaboul, D..

5 recordsLinked to original sources

bioRxiv2026

A subtype-specific gene regulatory program controls differential circuit integration of deep CA3 pyramidal neurons

How closely related neuronal subtypes integrate into different circuits remains poorly understood. Deep and superficial hippocampal CA3 pyramidal neurons (PNs) differ in intrinsic firing and mossy fiber (MF) input at specialized postsynaptic structures termed thorny excrescences (TEs). Combining developmental single-nucleus multiomics with genetic targeting, morphological analysis and electrophysiology, we identify the transcription factor ST18 as a regulator of deep CA3 subtype identity. ST18 marks sparsely thorny and burst-firing neurons, and gene regulatory analyses predict that it represses a superficial-associated program involved in dendritic spine development, synaptic organization, and electrophysiological properties. Postnatal ST18 loss shifts the transcriptional and chromatin landscape of deep CA3 PNs toward a superficial-like state. These molecular changes are accompanied by increased TE elaboration approaching superficial levels, enhanced excitatory synaptic activity, and reduced burst-firing. Together, these findings identify ST18-dependent restriction of an alternative subtype program as a mechanism linking molecular identity to distinct input connectivity patterns and intrinsic firing properties during postnatal circuit maturation.

neuroscience↗

bioRxiv2026

Multimodal profiling and intersectional genetics reveal CA1 border inhibitory neuron diversity and postnatal emergence of retrosplenial connectivity

Inhibitory neurons (INs) at the stratum radiatum/stratum lacunosum-moleculare border of hippocampal CA1 comprise diverse populations, including long-range-projecting neurons that innervate the retrosplenial cortex (RSCtx). However, their molecular organization and developmental connectivity remain poorly understood. Here, we combine multimodal transcriptomic profiling, intersectional genetics, and retrograde tracing to characterize CA1 border INs. We identified two major caudal ganglionic eminence-derived, Cxcl14-enriched populations distinguished by Syt6/Cck-related and Ntng1-expressing transcriptional profiles. We then generated a Cxcl14-Cre mouse line that, when combined with an IN-specific viral enhancer, provides genetic access to CA1 border INs. Retrograde labeling established that CA1 INs projecting to the RSCtx belong to the Ntng1-expressing population, and that this long-range projection emerges during postnatal mouse development, between postnatal days 3 and 5. Finally, analysis of genes encoding cell-surface proteins, key regulators of connectivity, revealed distinct expression profiles in RSCtx-projecting and SYT6-positive INs. Together, these findings establish a molecular and developmental framework for CA1 border IN diversity and provide a genetic strategy for investigating the assembly and function of these inhibitory circuits.

neuroscience↗

bioRxiv2025

Intrabody-guided synapse proteomics defines pyramidal neuron input architecture and uncovers early remodeling in a mouse model of Alzheimer's disease

Across their proximal and distal dendritic domains, pyramidal neurons (PNs) integrate inputs that differ in morphology and function. Hippocampal CA1 PNs are among the earliest affected neurons in Alzheimers disease (AD), but the molecular composition of their inputs and selective vulnerability remain poorly defined. We develop an intrabody-guided proximity-labeling strategy that targets the biotin ligase TurboID to endogenous postsynaptic scaffolds for cell-autonomous mapping of postsynaptic proteomes. Targeting PSD95 or Homer1 enables selective labeling of excitatory postsynaptic proteins in mouse CA1 PNs and resolves subsynaptic organization by comparing the two probes. Mapping the proteomes of major CA1 inputs uncovers a proximal-distal molecular logic that underlies their distinct properties. Applying this approach in the AppNL-G-F AD mouse model reveals an early signaling-driven phase of synaptic remodeling followed by a later translation-linked phase, with persistent downregulation of glutamatergic components. These results provide a molecular atlas of CA1 PN inputs and identify stage-specific mechanisms of synaptic vulnerability in early AD.

neuroscience↗

bioRxiv2025

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 Bcl6 as a regulator of pre- and postsynaptic structural maturation, and Smad3 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.

neuroscience↗

bioRxiv2022

TAOK2β represses translation via phosphorylation of eEF2 and ameliorates exaggerated protein synthesis in a mouse model of 16p11.2 microdeletion-driven autism

Microdeletions in the 16p11.2 region of the human genome are frequently associated with autism spectrum disorders (ASDs), but how these genomic rearrangements cause ASD remains unclear. Here, we reveal that TAOK2{beta}, a protein isoform encoded by the human TAOK2 gene located in the 16p11.2 locus, regulates mRNA translation. To identify key functional interaction partners of TAOK2{beta}, we performed proteomic screening from Neuro-2a (N2a) cells, mouse cortices, and cultured neurons. This revealed translation factors as a major class of enriched interacting proteins. Consistently, TAOK2{beta} is present in mouse cortical polyribosomes and cortices from Taok2 knockout mice show increased ribosome density on mRNAs and enhanced protein synthesis. Several lines of evidence support an effect of TAOK2{beta} on translation elongation via phosphorylation of eukaryotic elongation factor (eEF2). TAOK2 can directly phosphorylate eEF2 on Threonine 56 and this phosphorylation is reduced in cortices from Taok2 knockout mice. TAOK2{beta} WT overexpression increased eEF2 phosphorylation levels and reduced protein synthesis, whereas a kinase-dead allele of TAOK2{beta} showed opposite effects. Finally, we show that cortices from the mouse model of the human 16p11.2 microdeletion have increased polysome/monosome (P/M) ratios and protein synthesis, phenocopying Taok2 loss of function. Importantly, defective translation phenotypes observed in the mouse 16p11.2 microdeletion model of ASD could be normalized either by reintroducing Taok2 in vivo or by delivering TAOK2{beta} to cortical neurons derived from 16p11.2 microdeletion mice. Our results uncover a critical role of TAOK2{beta} as a regulator of protein synthesis and support the idea that translational control is a common endpoint of ASD-associated signaling pathways.

neuroscience↗