Nusrath Yusuf

Animal chemosensory systems discriminate between complex mixtures of chemical compounds by leveraging large repertoires of chemoreceptor proteins. To organize information from many receptors, these systems often employ a one-receptor-type per cell organization (Fulton et al. 2024). This structure requires a gene regulatory mechanism that can coordinate the generation of many distinct types of sensory neurons, each expressing a different receptor (Yusuf and Monahan 2024; Danoff et al. 2025; Pourmorady and Lomvardas 2022; Bashkirova and Lomvardas 2019; Monahan and Lomvardas 2015; Brann and Datta 2020). Here we show that testis-expressed gene 15 ( Tex15 ) is a critical component in an epigenetic mechanism that safeguards diverse olfactory receptor (OR) choice in the mouse olfactory system. Tex15 is required to inhibit an initial wave of olfactory receptor gene transcription that occurs as olfactory sensory neuron progenitors differentiate. In Tex15 knockout ( Tex15-/- ) mice, this repression fails: the early-transcribed OR genes get expressed at abnormally high levels, get chosen at high rates, and come to dominate the neuronal population. This results in a profound reduction in the diversity of OR gene choice and disrupted spatial patterning of the olfactory epithelium, while maintaining the expression of one receptor per cell. These changes in OR gene expression are accompanied by reduced deposition of H3K9me3 heterochromatin on OR genes and the preferential formation of interchromosomal enhancer hubs around the dominant ORs. We propose that Tex15 directs a heterochromatin-based transcriptional repression mechanism that counter-balances early OR transcription, thereby preventing the heterogeneous onset of OR transcription from skewing OR choice.

The mouse vomeronasal organ (VNO) detects pheromones, which provide vital information needed to find a mate, detect predators, or alert to the presence of an intruder. Within the VNO, pheromones are sensed by two families of G-protein Coupled Receptors (GPCRs) the type 1 and type 2 vomeronasal receptors (V1Rs and V2Rs). However, little is known about the regulatory mechanisms that control the expression of V1R and V2R genes by vomeronasal sensory neurons (VSNs). Here we identify a transcriptional repressor, Testis-expressed gene 15 ( Tex15 ), that regulates vomeronasal receptor gene choice and is required for the proper functioning of the vomeronasal system in regulating male behavior. We find that Tex15 is transiently expressed by VSN precursors prior to strong VR gene expression. The absence of Tex15 results in a pervasive change in the expression of V1R and V2R genes, which results in a less diverse repertoire of VR expressing cells and includes a dramatic reduction in the expression of specific receptors that have been tied to intermale aggression. Accordingly, Tex15 knockout mice exhibit lowered activation in the Accessory Olfactory Bulb (AOB) after exposure to male odorants, and a loss of stereotyped aggression between male mice. Taken together, these results show that Tex15 plays a critical role in pheromone sensing by ensuring that VSNs express a diverse set of receptor proteins.

Summary: The mammalian sense of smell relies upon a vast array of receptor proteins to detect odorant compounds present in the environment. The proper deployment of these receptor proteins in olfactory sensory neurons is orchestrated by a suite of epigenetic processes that remodel the olfactory genes in differentiating neuronal progenitors. The goal of this review is to elucidate the central role of gene regulatory processes acting in neuronal progenitors of olfactory sensory neurons that lead to a singular expression of an odorant receptor in mature olfactory sensory neurons. We begin by describing the principal features of odorant receptor gene expression in mature olfactory sensory neurons. Next, we delineate our current understanding of how these features emerge from multiple gene regulatory mechanisms acting in neuronal progenitors. Finally, we close by discussing the key gaps in our understanding of how these regulatory mechanisms work and how they interact with each other over the course of differentiation.

Somatostatin interneurons are the earliest born population of cortical inhibitory cells. They are crucial to support normal brain development and function; however, the mechanisms underlying their integration into nascent cortical circuitry are not well understood. In this study, we begin by demonstrating that the maturation of somatostatin interneurons is activity dependent. We then investigated the relationship between activity, alternative splicing and synapse formation within this population. Specifically, we discovered that the Nova family of RNA-binding proteins are activity-dependent and are essential for the maturation of somatostatin interneurons, as well as their afferent and efferent connectivity. Within this population, Nova2 preferentially mediates the alternative splicing of genes required for axonal formation and synaptic function independently from its effect on gene expression. Hence, our work demonstrates that the Nova family of proteins through alternative splicing are centrally involved in coupling developmental neuronal activity to cortical circuit formation.

Summary: Cortical interneurons display a remarkable diversity in their morphology, physiological properties and connectivity. Elucidating the molecular determinants underlying this heterogeneity is essential for understanding interneuron development and function. We discovered that alternative splicing differentially regulates the integration of somatostatin- and parvalbumin-expressing interneurons into nascent cortical circuits through the cell-type specific tailoring of mRNAs. Specifically, we identified a role for the activity-dependent splicing regulator Rbfox1 in the development of cortical interneuron subtype specific efferent connectivity. Our work demonstrates that Rbfox1 mediates largely non-overlapping alternative splicing programs within two distinct but related classes of interneurons.