
The GTF2IRD1-transthyretin-ERK axis plays a critical role in the neurodevelopmental deficits observed in Williams Syndrome.


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Williams Syndrome (WS; OMIM#194050) is a rare disorder, which is caused by the microdeletion of one copy of 25-27 genes, and WS patients display diverse neuronal deficits. Although remarkable progresses have been achieved, the mechanisms for these distinct deficits are still largely unknown. Here, we have shown that neural progenitor cells (NPCs) in WS forebrain organoids display abnormal proliferation and differentiation capabilities, and synapse formation. Genes with altered expression are related to neuronal development and neurogenesis. Single cell RNA-seq (scRNA-seq) data analysis revealed 13 clusters in healthy control and WS organoids. WS organoids show an aberrant generation of excitatory neurons. Mechanistically, the expression of transthyretin (TTR) are remarkably decreased in WS forebrain organoids. We have found that GTF2IRD1 encoded by one WS associated gene GTF2IRD1 binds to TTR promoter regions and regulates the expression of TTR . In addition, exogenous TTR can activate ERK signaling and rescue neurogenic deficits of WS forebrain organoids. Gtf2ird1 deficient mice display similar neurodevelopmental deficits as observed in WS organoids. Collectively, our study reveals critical function of GTF2IRD1 in regulating neurodevelopment of WS forebrain organoids and mice through regulating TTR-ERK pathway.

### Competing Interest Statement

The authors have declared no competing interest.

A human forebrain organoid model reveals the essential function of GTF2IRD1-TTR-ERK axis for the neurodevelopmental deficits of Williams Syndrome

aberrant-neurogenesis-and-neurodevelopmental-deficits-in-a-human-forebrain-organoid-model-of-williams-syndrome


Aberrant Neurogenesis and Neurodevelopmental Deficits in a Human Forebrain Organoid Model of Williams Syndrome


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A subset of cerebellar nuclei neurons originates from an extrinsic germinal zone, potentially the mesencephalon, independently of the known cerebellar primordium germinal zones.


Cerebellar nuclei (CN) neurons serve as the primary output of the cerebellum and originate from the cerebellar primordium at the early stages of cerebellar development. Employing various methodologies, we have characterized a specific subset of CN neurons that do not originate from the rhombic lip and the ventricular zone of the cerebellar primordium. Embryos were collected from timed pregnant mice at early stages of development and processed for immunohistochemistry (IHC), Western blotting, in situ hybridization (ISH), embryonic culture, DiI labeling, or flow cytometry analysis (FCM). Our findings indicate that a subset of CN neurons expressing α-synuclein (SNCA), OTX2, MEIS2, and p75NTR (NGFR) are located in the rostro-ventral (rv) region of the nuclear transitory zone (NTZ), while CN neurons derived from the rhombic lip are positioned in the caudo-dorsal (cd) area of the NTZ in the cerebellar primordium. Utilizing Otx2-GFP and Atoh1-/- mice, we have determined that these cells do not originate from the germinal zone of the cerebellar primordium. These results suggest the existence of a novel extrinsic germinal zone for the cerebellar primordium, possibly the mesencephalon, from which early CN neurons originate.

SIGNIFICANCE STATEMENT The cerebellum contains a variety of distinct neuronal populations, each playing a significant role in its function within the brain. This research demonstrates that a particular subset of cerebellar nuclei neurons originates from a previously unrecognized germinal zone specific to the cerebellar primordium, independently of Atoh1’s influence.

### Competing Interest Statement

The authors have declared no competing interest.

IDENTIFICATION OF AN EARLY SUBSET OF CEREBELLAR NUCLEI NEURONS IN MICE

identification-of-a-novel-subset-of-cerebellar-nuclei-neurons-originating-from-the-mesencephalon-in-mice


Identification of a Novel Subset of Cerebellar Nuclei Neurons Originating from the Mesencephalon in Mice



Mutations in the PTEN gene lead to selective impairments in the development and function of inhibitory GABAergic neurons, while excitatory cholinergic neurons remain unaffected. Dietary supplementation with the ketone body β-hydroxybutyrate during early development can rescue these GABAergic deficits by inducing the activity of the FOXO transcription factor.


A finely tuned balance between excitation and inhibition (E/I) is essential for proper brain function. Disruptions in the GABAergic system, which alter this equilibrium, are a common feature in various types of neurological disorders, including Autism Spectrum Disorders (ASDs).

Mutations in PTEN, the main negative regulator of the PI3K/Akt pathway, are strongly associated with ASD. However, it is unclear whether PTEN deficiencies can differentially affect inhibitory and excitatory signaling. Using the C. elegans neuromuscular system, where both excitatory (cholinergic) and inhibitory (GABAergic) inputs regulate muscle activity, we found that daf-18 / PTEN mutations specifically impact GABAergic (but not cholinergic) neurodevelopment and function. This selective impact results in a deficiency in inhibitory signaling. The specific defects observed in the GABAergic system in daf-18/PTEN mutants are due to reduced activity of DAF-16/FOXO during development. Ketogenic diets (KGDs) have proven effective for disorders associated with E/I imbalances. However, the mechanisms underlying their action remain largely elusive. Importantly, we found that a diet enriched with the ketone body β-hydroxybutyrate during early development induces DAF-16/FOXO, therefore improving GABAergic neurodevelopment and function in daf-18/PTEN mutants. Our study provides fundamental insights linking PTEN mutations and neurodevelopmental defects and delves into the mechanisms underlying KGDs’ positive effects on neuronal disorders characterized by E/I imbalances.

Highlights 

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### Competing Interest Statement

The authors have declared no competing interest.

 [1]: pending:yes

The ketone body β-hydroxybutyrate rescues neurodevelopmental deficits in the GABAergic system of daf-18/PTEN Caenorhabditis elegans mutants

dietary-ketone-body-supplementation-rescues-gabaergic-deficits-in-c-elegans-pten-mutants


Dietary Ketone Body Supplementation Rescues GABAergic Deficits in C. elegans PTEN Mutants



The author explores the impact of Protocadherin10 deficiency in interneurons on socio-affective communication, particularly in relation to Autism Spectrum Disorder.


Autism Spectrum Disorder (ASD) is a group of neurodevelopmental conditions associated with deficits in social interaction and communication, together with repetitive behaviors. The cell adhesion molecule Protocadherin10 ( Pcdh10 ) has been implicated in the etiology of ASD. Pcdh10 is expressed in the nervous system during embryonic and early postnatal development and has been linked to neural circuit formation. Here, we show strong expression of Pcdh10 in the ganglionic eminences and in the basolateral complex of the amygdala at mid and late embryonic stages, respectively. Both inhibitory and excitatory neurons expressed Pcdh10 in the basolateral complex at perinatal stages and genes linked to vocalization behavior were enriched in Pcdh10- expressing neurons in adult mice. To further investigate the involvement of Pcdh10 in neurodevelopment with relevance to ASD, and to assess the functional and behavioral consequences of loss of Pcdh10 in basolateral amygdala interneurons, we combined a ubiquitous and a conditional Pcdh10 knockout mouse model. Conditional knockout of Pcdh10 reduced the number of interneurons in the basolateral complex. Both models exhibited altered developmental trajectories of socio-affective communication through isolation-induced ultrasonic vocalizations in neonatal pups, characterized by increased emission rates in heterozygous pups. Furthermore, acoustic call features were affected and heterozygous conditional knockout pups emitted calls characterized by reduced peak frequencies but increased frequency modulation. Additionally, we identified distinct clusters of call subtypes with specific developmental trajectories, suggesting the vocalization repertoire is extensive and dynamic during early life. The nuanced alterations in socio-affective communication at the level of call emission rates, acoustic call features, and clustering of call subtypes were primarily seen in heterozygous pups of the conditional knockout and less prominent in the ubiquitous Pcdh10 knockout, suggesting that changes in anxiety levels associated with Gsh2 -lineage interneurons might drive the observed behavioral effects. Together, this demonstrates that loss of Pcdh10 specifically in interneurons contributes to behavioral alterations in socio-affective communication with relevance to ASD.

### Competing Interest Statement

The authors have declared no competing interest.

*   ASD
    :   Autism Spectrum Disorder
    BLA
    :   Basolateral Amygdala
    BLC
    :   Basolateral complex
    BP
    :   Biological process
    CGE
    :   Caudal ganglionic eminence
    cKO
    :   Conditional knockout
    Ctx
    :   Cortex
    dBFS
    :   Decibels relative to full-scale
    E
    :   Embryonic day
    GABA
    :   Gamma-aminobutyric acid
    GEs
    :   Ganglionic eminences
    GO
    :   Gene ontology
    HCR
    :   Hybridization chain reaction
    He
    :   Heterozygous
    Ho
    :   Homozygous
    HypTh
    :   Hypothalamus
    ISH
    :   In situ hybridization
    KDE
    :   Kernel density estimation
    KO
    :   knockout
    LA
    :   Lateral amygdala
    LGE
    :   Lateral ganglionic eminence
    MGE
    :   Medial ganglionic eminence
    MZ
    :   Mantle zone
    nLOT
    :   Nucleus of the lateral olfactory tract
    NRTC
    :   Non-reverse transcriptase control
    NTC
    :   Non-template control
    P
    :   Postnatal day
    PAG
    :   Periaqueductal grey
    PBS
    :   Phosphate-buffered saline
    Pcdh10
    :   Protocadherin10
    PCR
    :   Polymerase chain reaction
    PFA
    :   Paraformaldehyde
    POA
    :   Preoptic area
    PVDF
    :   Polyvinylidene difluoride
    qPCR
    :   quantitative polymerase chain reaction
    Spt
    :   Septum
    SVZ
    :   Subventricular zone
    Th
    :   Thalamus
    TRN
    :   Thalamic reticular nucleus
    USV
    :   Ultrasonic vocalization
    VMS
    :   Ventropallial migratory stream
    VZ
    :   Ventricular zone
    Wt
    :   Wild-type
    ZI
    :   Zona incerta

Altered Socio-Affective Communication and Amygdala Development in mice with Protocadherin10-deficient Interneurons

impact-of-protocadherin10-on-mouse-amygdala-development-and-communication


Impact of Protocadherin10 on Mouse Amygdala Development and Communication



The author argues that the assembly of neuron- and radial glial cell-derived ECM molecules, specifically NCAN, TNC, and HA, plays a crucial role in promoting radial migration during cortical development.


Radial neuronal migration is a key neurodevelopmental event for proper cortical laminar organization. The multipolar-to-bipolar transition, a critical step in establishing neuronal polarity during radial migration, occurs in the subplate/intermediate zone (SP/IZ), a distinct region of the embryonic cerebral cortex. It has been known that the extracellular matrix (ECM) molecules are enriched in the SP/IZ. However, the molecular constitution and functions of the ECM formed in this region remain poorly understood. Here, we identified neurocan (NCAN) as a major chondroitin sulfate proteoglycan in the SP/IZ. NCAN binds to both radial glial cell-derived tenascin-C (TNC) and hyaluronan (HA), a large linear polysaccharide, forming a ternary complex of NCAN, TNC, and HA in the SP/IZ. Developing cortical neurons make contact with the ternary complex during migration. The enzymatic or genetic disruption of the ternary complex impairs radial migration by suppressing the multipolar-to-bipolar transition. Furthermore, both TNC and NCAN promoted the morphological maturation of cortical neurons in vitro . The present results provide evidence for the cooperative role of neuron- and radial glial cell-derived ECM molecules in cortical development.

### Competing Interest Statement

The authors have declared no competing interest.

Assembly of neuron- and radial glial cell-derived extracellular matrix molecules promotes radial migration of developing cortical neurons

assembly-of-neuron-and-radial-glial-cell-derived-ecm-molecules-in-cortical-development


Assembly of Neuron- and Radial Glial Cell-Derived ECM Molecules in Cortical Development
