Biology subjects

Kovner, R.

Publications and source records attributed to Kovner, R..

5 recordsLinked to original sources

bioRxiv2025

A Retinoic Acid Autoregulatory Loop Governing Prefrontal-Motor Arealization

The frontal lobe comprises the prefrontal association cortex (PFC), which supports complex cognition and goal-directed behavior, and the motor cortex (MC), which executes movement. A hallmark of primate brain evolution is PFC expansion accompanied by a posterior displacement of the MC. Retinoic acid (RA) signaling has emerged as a key regulator of PFC specification and expansion. However, the mechanisms that spatially confine RA signaling within the developing PFC, and the downstream RA-responsive gene networks, remain poorly understood. Here we defined an RA-associated gene regulatory network (RA-GRN) in the developing human PFC and identified MEIS2, which encodes a transcription factor linked to intellectual disability and autism spectrum disorder (ASD), as its key hub of this network. Conditional deletion of Meis2 in postmitotic cortical excitatory neurons in mice results in a partial respecification of prospective prefrontal association territories toward motor-like molecular and connectional features, highlighting a critical role of postmitotic neurons in establishing and maintaining cortical areal identities. Concomitant with Meis2 loss, the population of excitatory neurons expressing the RA-synthesizing enzyme ALDH1A3, and consequently RA signaling itself, is markedly reduced in the developing medial prefrontal cortex (mPFC). These findings revealed a conserved autoregulatory loop: RA [->] MEIS2 [->] ALDH1A3 [->] RA that reinforces a PFC-enriched RA gradient and organizes the MC-PFC axis. Together, our findings reveal a postmitotic mechanism by which specific features of neuronal identity reinforce RA signaling to define key features of prefrontal and motor cortical territories, linking a classic morphogen to transcriptional identity, neural circuit formation and function, and potentially to psychiatric disorders.

neuroscience↗

bioRxiv2025

Human-specific features of the cerebellum and ZP2-regulated synapse development

Understanding the unique features of the human brain compared to non-human primates has long intrigued humankind. The cerebellum refines motor coordination and cognitive functions, contributing to the evolutionary development of human adaptability and dexterity. To identify shared and divergent features across primates, we conducted single-nucleus transcriptomic and chromatin accessibility profiling of the adult cerebellar cortex in humans, chimpanzees, macaques, and marmosets. We revealed human-specific transcriptomic and regulatory features, particularly those involved in synaptogenesis. Notably, we identified an enrichment of the sperm receptor zona pellucida glycoprotein 2 (ZP2) and its potential interactors, known for their roles in gamete interaction, in human granule cells. Experimental data show that ZP2 expression in human granule cells is induced by pontine mossy fibers, reducing synaptic proteins at pontocerebellar glomerular synapses, and decreasing cerebellar neuron electrophysiological activity. This unexpected co-option of ZP2 in human-specific synapse regulation provides insights into the evolutionary specialization of the human cerebellum.

neuroscience↗

bioRxiv2024

Molecular Specification of Claustro-Amygdalar and Paleocortical Neurons and Connectivity

The ventropallial excitatory neurons (ExNs) in the claustro-amygdalar complex and piriform cortex (PIR; part of paleocortex) form crucial reciprocal connections with the prefrontal cortex (PFC), integrating cognitive and sensory information that result in adaptive behaviors. Early-life disruptions in these circuits are linked to neuropsychiatric disorders, highlighting the importance of understanding their development. Our study uncovers that transcription factors SOX4, SOX11, and TFAP2D play a pivotal role in the development, identity, and PFC connectivity of these neurons. Using mouse models, we demonstrate that the absence of transcription factors SOX4 and SOX11 in post-mitotic ExNs dramatically reduces the size of the basolateral amygdala complex (BLC), claustrum, and PIR. SOX4 and SOX11 control BLC formation through direct regulation of Tfap2d expression. Cross-species analyses, including humans, identified conserved Tfap2d expression in developing ExNs of BLC, claustrum, paleocortex including PIR, and the associated transitional areas of the frontal, insular and temporal cortex. While the loss and haploinsufficiency of Tfap2d yield similar alterations in learned threat behaviors, differences emerge in the manifestation of Tfap2d dosage, particularly in terms of changes observed in BLC size and the connectivity pattern between the BLC and PFC. This underscores the significance of Tfap2d dosage in orchestrating developmental shifts in BLC-PFC connectivity and behavioral modifications reminiscent of symptoms of neuropsychiatric disorders. Together, these findings reveal key elements of a conserved gene regulatory network that shapes the development and function of crucial ventropallial ExNs and their PFC connectivity and offer insights into their evolution and alterations in neuropsychiatric disorders.

neuroscience↗

bioRxiv2022

A cross-species proteomic map of synapse development reveals neoteny during human postsynaptic density maturation

The molecular mechanisms and evolutionary changes accompanying synapse development are still poorly understood. Here, we generated a cross-species proteomic map of synapse development in the human, macaque, and mouse neocortex. By tracking the changes of >1,000 postsynaptic density (PSD) proteins from midgestation to young adulthood, we found that PSD maturation in humans separates into three major phases that are dominated by distinct pathways. Cross-species comparisons reveal that the human PSD matures about two to three times slower than other species and contains higher levels of Rho guanine nucleotide exchange factors (RhoGEFs) in the perinatal period. Enhancement of the RhoGEF signaling in human neurons delays the morphological maturation of dendritic spines and the functional maturation of synapses, potentially contributing to the neotenic traits of human brain development. In addition, PSD proteins can be divided into four modules that exert stage- and cell type-specific functions, possibly explaining their differential associations with cognitive functions and diseases. Together, our proteomic map of synapse development provides a blueprint for studying the molecular basis and evolutionary changes of synapse maturation.

neuroscience↗

bioRxiv2019

Transcriptional Profiling of Primate Central Nucleus of the Amygdala Neurons to Understand the Molecular Underpinnings of Early Life Anxious Temperament

Children exhibiting extreme anxious temperament (AT) are at an increased risk to develop anxiety and depression. Work in young rhesus monkeys mechanistically links the central nucleus of the amygdala (Ce) to AT. Here, we used laser capture microscopy and RNA sequencing in 47 young rhesus monkeys to investigate AT s molecular underpinnings by focusing on lateral Ce (CeL) neurons. We found 528 AT-related transcripts, including protein kinase C type-delta (PKC{delta}), a CeL microcircuit cell marker implicated in rodent threat processing. We characterized PKC{delta} neurons in the rhesus CeL, compared their distribution to the mouse, and demonstrated that a subset of these neurons project to the laterodorsal bed nucleus of the stria terminalis (BSTLd). These findings present evidence in the primate of a CeL to BSTLd circuit that maybe relevant to understanding human anxiety and points to specific molecules within this circuit that could serve as potential treatment targets for anxiety disorders.

neuroscience↗