Mutant Huntingtin disrupts neurogenic and astroglial programs via the EZH2-Let-7g-LIN28 axis with rescue by epigenetic modulators.

Central Thyroid Hormone Deprivation Disrupts Cortical Cilia and Oligodendrocyte Lineage in an Allan–Herndon–Dudley Syndrome Mouse Model

Background: Allan–Herndon–Dudley syndrome (AHDS) is an X-linked neurodevelopmental disorder caused by loss of the thyroid hormone (TH) transporter MCT8, resulting in central TH deprivation and disrupted cortical maturation, cognition, and motor control. MCT8/OATP1C1 double-knockout (dKO) mice faithfully model the human disease, recapitulating its postnatal hypomyelination, neuromotor impairment, and cortical defects. Yet, cell-type–specific pathologies underlying AHDS remain insufficiently defined. Methods: To uncover cellular perturbations by TH deprivation, we performed single-nucleus RNA sequencing on cortex and attached cerebral nuclei from P21 WT and dKO mice. Differential gene expression, trajectory, pseudotime and gene-set enrichment analyses, and NeuronChat-based cell–cell communication modeling were integrated with LC-MS/MS-based TH quantification, immunofluorescence, and RNAscope. Results: In 48 clusters identified across cortical and striatal regions, we found increased numbers of GABAergic striatal D1 and D2 neurons in dKO mice, whereas mature oligodendrocytes were reduced. Trajectory analysis uncovered a bifurcation within the oligodendrocyte lineage, separating WT and dKO maturation paths and producing a dKO branch with gene profiles reminiscent of a stress-responsive, demyelination-prone state, despite largely preserved expression of core myelination genes. Trajectory analyses revealed shifted pseudotime states and distinct gene expression profiles in glutamatergic intratelencephalic and corticothalamic lineages of dKO mice. Differential gene expression patterns showed limited correspondence to Slc16a2 or Slco1c1 transcript levels but aligned strongly with published TH deprivation datasets, validating our findings and indicating that cellular perturbations are largely established by P21. Cell–cell communication analysis revealed a network imbalance favoring GABAergic over glutamatergic signaling, accompanied by altered neurexin–neuroligin interactions. In parallel, we identified a coordinated dysregulation of cilia-related genes, together with changes in cilia length and number. Conclusions: Our findings provide the first single-cell–level cortical map of AHDS brain pathology, revealing cilia defects, excitation–inhibition imbalance, differing pseudotime trajectories in glutamatergic neuronal populations and altered oligodendrocyte maturation, with actionable candidate genes such as Lama2, Litaf, and Dcc, as promising targets for future mechanistic and therapeutic exploration in AHDS. Slc16a2 and Slco1c1 transcript abundance alone did not predict cellular vulnerability, highlighting TH availability rather than transporter expression as key determinant of cell-type sensitivity and core mechanism for cortical network homeostasis. Graphical abstract

Characterization of Astrocyte Density in the Pitt–Hopkins Syndrome Mouse Model of Autism Spectrum Disorder

Germline heterozygous TCF4 LOF, which models PTHS, does not appear to significantly affect the astrocyte lineage at the cell population level, and germline heterozygous Tcf4 LOF did not result in misallocation of ventrally derived astrocytes into the dorsal cortex.

NSD2 Coordinates the Neurogenic‐to‐Gliogenic Transition via H3K36me2‐Dependent Activation of the EGFR‐ERK Pathway

ABSTRACT Haploinsufficiency of the histone methyltransferase NSD2 is a major cause of Wolf‐Hirschhorn syndrome (WHS) and the related Rauch‐Steindl syndrome (RAUST), both of which exhibit microcephaly and intellectual disability. However, the precise role of NSD2 in brain development remains unclear. Here, we identify NSD2 as a pivotal epigenetic regulator orchestrating the transition from neurogenesis to gliogenesis in the developing mouse neocortex. Conditional knockout of Nsd2 severely impairs astrocyte production in late embryogenesis, while its overexpression promotes astrocytic fate. Integrated epigenomic and transcriptomic analyses reveal that NSD2 deposits the activating histone mark H3K36me2 directly at the Egfr promoter, sustaining EGFR expression and downstream ERK signaling—a pathway essential for gliogenesis. Pharmacological activation of ERK phosphorylation rescues the astrogliogenesis defects both in vitro and in vivo. Notably, Nsd2‐deficient mice exhibit significant deficits in learning and memory. Our findings define an NSD2‐H3K36me2‐EGFR‐ERK axis that drives cortical gliogenesis and provide mechanistic insights into the potential contribution of NSD2 deficiency to neurodevelopmental abnormalities.

Huntingtin is a cell-autonomous regulator of neuropeptide trafficking and clock output

SYNGAP1 haploinsufficiency disrupts early neurodevelopment and accelerates intrinsic neuronal maturation in human patient-derived models

It is demonstrated that SYNGAP1 haploinsufficiency disrupts early human brain development and accelerates intrinsic neuronal maturation, with pathogenic mechanisms emerging before synaptogenesis and extending beyond SYNGAP1’s established synaptic role.

Delayed astrocyte development impairs Sema6a-Plxna2/4-mediated astrocyte-neuron crosstalk and causes depressive-like behavior

Neural functions and circuit formation rely on intricate crosstalk among various cell types during critical periods. Disruptions or delays in this crosstalk between neurons and astrocytes lead to abnormal neural functions and neurodevelopmental disorders. However, the lack of robust mouse models to study the crosstalk between astrocytes and neurons thus renders unclear the implications of impeding such interactions. In this study, we demonstrate that Egfr knockout during the critical period of neuronal maturation results in a transient absence of astrocytes, with recovery observed in adult mice. This model thus provides a unique opportunity to investigate the effects of impaired astrocyte-neuron communication during development. Mechanically, we show that loss of Egfr disrupts the Egfr-pERK-Epb41l2 signaling axis, which in turn prevents glial progenitor cells from migrating outward. More importantly, Egfr deficiency during the critical period compromises astrocyte-neuron communication via the Sema6a-Plxna2/4 ligand-receptor pair. This impaired intercellular crosstalk reduces neuronal dendritic complexity and excitability, ultimately culminating in depressive-like behaviors in adult mice. This study shows that developmental disruption of EGFR signaling leads to transient astrocyte loss and impaired astrocyte–neuron crosstalk. Altered EGFR–pERK–EPB41L2 signaling and Sema6a–Plxna2/4 communication, results in reduced dendritic complexity, neuronal excitability, and long-term depressive-like behaviours.