Biology subjects

Albizzati, E.

Publications and source records attributed to Albizzati, E..

3 recordsLinked to original sources

bioRxiv2026

Selective vulnerability of excitatory cortical neurons to ZMYND11 loss reveals cell-type-specific mechanisms of neurodevelopmental disorder risk

Excitation/inhibition (E:I) imbalance is a convergent mechanism in neurodevelopmental disorders (NDDs), yet whether NDD risk genes disrupt excitatory and inhibitory neurons through shared or distinct molecular programs remains poorly understood. Using human pluripotent stem cell-derived cortical projection and medial ganglionic eminence-like inhibitory neurons, we show that loss-of-function mutations in the chromatin reader ZMYND11 produce cell-type-selective vulnerability in cortical excitatory neurons. ZMYND11-deficient excitatory neurons exhibit hyperexcitability accompanied by de-repression of BMP signaling, dysregulation of glutamate receptor expression, and a shift toward non-brain splicing isoforms, whereas these molecular signatures are largely absent in ZMYND11-deficient inhibitory neurons. This cell-type selectivity is associated with differential upregulation of RBFOX family splicing regulators. Structure-function analysis reveals that MYND domain is required for normal progenitor dynamics and neuronal excitability. Together, these findings indicate that E:I imbalance in ZMYND11-associated NDD arises primarily from cell-type-selective vulnerability of excitatory cortical projection neurons and identify MYND domain as a critical determinant of neuronal function. HighlightsO_LIZMYND11-deficient excitatory neurons (ExNs) show hyperexcitability. C_LIO_LIAltered BMP signaling & glutamate receptor levels are implicated in mutant ExNs. C_LIO_LIInhibitory neurons show attenuated response to ZMYND11 loss. C_LIO_LIThe MYND domain in ZMYND11 is a critical regulator of neuronal excitability. C_LI

neuroscience↗

bioRxiv2025

Dose-dependent NFI regulation of progenitor lifespan and output underlying human neocortical malformation

Nuclear Factor I (NFI) misexpressions in humans are associated with severe brain malformations, yet the underlying mechanisms remain poorly understood. Here we show that NFIs regulate the broad lineage progression and lifespan of radial glial progenitors (RGPs), and consequently neocortical development in a dose-dependent manner. Human cerebral organoids carrying patient-mimicking NFI mutations exhibit expression level-dependent bidirectional impairments in RGP temporal development, coinciding with patient phenotypes. In mouse models, selective removal of NFIs leads to a dramatic protraction of RGP lineage progression and lifespan, excessive progeny output, and neocortical overgrowth and abnormal folding, whereas overexpression of NFIs accelerates RGP lineage progression, resulting in developmental stage-dependent precocious productions of diverse neural progenies. Moreover, NFIs exhibit a positive auto-regulation and progressive increase in expression, and regulate distinct temporal-specific targets underlying RGP lineage progression. These results suggest that NFIs act as evolutionarily conserved key global temporal regulators of RGP lineage progression and neocortical development. HIGHLIGHTSO_LINFIs affect human RGP temporal development coinciding with patient phenotypes. C_LIO_LINFI removal protracts RGP lineage progression and lifespan with excessive progeny output. C_LIO_LINFI overexpression accelerates RGP lineage progression with precocious progeny output. C_LIO_LINFIs regulate distinct temporal-specific targets underlying RGP lineage progression. C_LI

neuroscience↗

bioRxiv2023

Mecp2 knock-out astrocytes affect synaptogenesis by IL-6 dependent mechanisms

Synaptic abnormalities represent a hallmark for several neurological diseases and clarification of the underlying mechanisms constitutes a crucial step towards the development of therapeutic strategies. Rett syndrome (RTT) is a rare neurodevelopmental disorder, mainly affecting females, caused by heterozygous mutations in the X-linked Methyl-CpG-Binding Protein 2 (MECP2) gene, leading to a deep derangement of synaptic connectivity. Although initial studies have supported the exclusive involvement of neurons, recent data have highlighted the pivotal contribution of astrocytes in RTT pathogenesis through non-cell autonomous mechanisms. Since astrocytes regulate synaptogenesis by releasing multiple molecules, we investigated the influence of soluble factors secreted by Mecp2 KO astrocytes on synaptic density. We found that Mecp2 deficiency in astrocytes negatively affects their ability to support synapse formation by releasing synaptotoxic molecules, among which we identified interleukin-6 (IL-6). Notably, aberrant IL-6 expression exclusively emerges from a dysfunctional astrocyte-neuron crosstalk, and blocking IL-6 activity prevents synaptic alterations.

neuroscience↗