Biology subjects

LaMantia, A.-S.

Publications and source records attributed to LaMantia, A.-S..

3 recordsLinked to original sources

bioRxiv2025

Distinct cellular and transcriptional mechanisms mediate an antioxidant therapeutic response in 22q11-deleted upper layer cortical projection neurons

We characterized cellular and molecular mechanisms underlying the therapeutic response in vitro and in vivo to the antioxidant N-acetyl cysteine (NAC), which in the LgDel 22q11.2 Deletion Syndrome mouse model restores growth and connectivity of upper layer cortical projection neurons (Layer 2/3 PNs) and improves cognitive performance. NAC treatment of primary cultured LgDel L 2/3 PNs does not restore these neurons to a wild type (WT) state. Rather than returning to the bimodal dendrite and axon size distribution seen in WT, LgDel L 2/3 PN dendrite and axon growth in vitro increases unimodally in response to NAC. In parallel, altered expression of 22q11-deleted genes and presumed downstream targets are unchanged. Instead, novel antioxidant defense and neuronal growth genes are differentially expressed: some generally NAC-regulated, others responsive only in the context of 22q11 deletion. Apparently, NAC ameliorates L 2/3 PN developmental pathology without restoring WT cell states or typical expression of mutant genes or their downstream targets. NAC also elicits differential expression of antioxidant defense genes in 22q11-deleted L 2/3 PNs--but not L 5/6 counterparts--in the developing postnatal LgDel mouse cortex, rather than modulating 22q11 genes or downstream targets. These NAC-dependent, L 2/3 PN-selective in vivo cellular and transcriptional changes differ substantially from those in primary culture. Thus, despite some in vitro and in vivo parallels, the NAC therapeutic response that diminishes oxidative stress-related L 2/3 PN circuit and behavioral pathology due to 22q11 deletion has a unique in vivo signature.

neuroscience↗

bioRxiv2025

22q11 deletion selectively alters progenitor states and projection neuron identities in the developing cerebral cortex

The developmental origin of Layer 2/3 projection neuron (PN) pathology in the frontal association cortex due to heterozygous 22q11 gene deletion--the genetic foundation of elevated risk for schizophrenia and related psychiatric disorders in 22q11.2 Deletion Syndrome (22q11DS)--reflects cell state-dependent, temporally restricted vulnerability of transcriptionally diverse subsets of intermediate progenitors and neuroblasts. The molecular and cell biological consequences of these evanescent state-dependent changes include divergent proliferative capacity of the most highly proliferative progenitors, enhanced neurogenic gene expression, altered DNA methylation, and increased numbers of immediate neuroblast progeny at peak neurogenesis in fetal frontal cortex of the LgDel 22q11DS mouse model. These altered cell states prefigure a post-natal cohort of upper layer PNs generated at the peak of Layer 2/3 PN genesis--not before or after--whose frequencies are significantly diminished and molecular identities are substantially divergent in medial frontal association, but not primary somatosensory or visual cortices. Thus, frontal association cortices in 22q11DS and schizophrenia more broadly may be pathogenic targets due to vulnerabilities of expanded, highly proliferative, transcriptionally dynamic populations of intermediate progenitors that increase L2/3 PN frequency to enhance cortico-cortical connectivity.

neuroscience↗

bioRxiv2021

Lineage, Identity, and Fate of Distinct Progenitor Populations in the Embryonic Olfactory Epithelium

We defined a temporal dimension of precursor diversity and lineage in the developing mouse olfactory epithelium (OE) at mid-gestation that results in genesis of distinct cell classes. Slow, symmetrically dividing Meis1+/ Pax7+ progenitors in the early differentiating lateral OE give rise to small numbers of Ascl1+ precursors in the dorsolateral and ventromedial OE. Few of the initial progeny of the Ascl1+ precursors immediately generate olfactory receptor neurons (ORNs). Instead, most early progeny of this temporally defined precursor cohort, labeled via temporally discreet tamoxifen-dependent Ascl1Cre-driven recombination, populate a dorsomedial OE domain comprised of proliferative Ascl1+ as well as Ascl1-cells from which newly generated ORNs are mostly excluded. The most prominent early progeny of these Ascl1+ OE precursors are migratory mass cells associated with the nascent olfactory nerve (ON) in the frontonasal mesenchyme. These temporal, regional and lineage distinctions are matched by differences in proliferative capacity and modes of division in isolated, molecularly distinct lateral versus medial OE precursors. By late gestation, the progeny of the temporally and spatially defined Ascl1+ precursor cohort include few proliferating precursors. Instead, these cells generate a substantial subset of OE sustentacular cells, spatially restricted ORNs, and ensheathing cells associated with actively growing as well as mature ON axons. Accordingly, from the earliest stages of OE differentiation, distinct temporal and spatial precursor identities provide a template for acquisition of subsequent OE and ON cellular diversity.

developmental biology↗