Modifying PCDH19 levels affects cortical interneuron migration

Pancho, Anna; Mitsogiannis, Manuela D.; Aerts, Tania; Vecchia, Marco Dalla; Ebert, Lena; Geenen, Lieve; Noterdaeme, Lut; Vanlaer, Ria; Stulens, Anne; Hulpiau, Paco; Staes, Katrien; Roy, Frans van; Dedecker, Peter; Schermer, Bernhard; Seuntjens, Eve

doi:10.3389/fnins.2022.887478

Cited by 12 publications

(15 citation statements)

References 83 publications

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“…However, residual clustering and limited migration away from the injection site have also been reported 29,33 . Since factors transiently expressed in developing brain e.g., clustered gamma-protocadherins 34,35 or CCCTC-binding factor 36 can influence migration and integration of MGE progenitor cells, we here investigated integration following transplantation into recipient mice at different developmental ages. Because factors 10 expressed in local microcircuits e.g., vesicular GABA transporters 32 or MTG8 37 can also influence integration of these progenitors, we compared transplantations into cortex and hippocampus (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Second, precursors for MGE-derived interneuron subtypes could be subject to programmed cell death during neurodevelopment. This process is regulated by region-specific expression of environmental factors like pcdh 34,35,49 , c-Maf 50 or PTEN 44 which facilitate postnatal survival and/or maturation of PV+ and SST+ interneurons. Given that these are developmentally regulated expression patterns it is not surprising that juvenile and adult brains were less receptive to integration of transplanted MGE progenitors than mouse pups or the differences in PV/SST ratios seen here (Fig 4).…”

Section: Discussionmentioning

confidence: 99%

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Host brain environmental influences on transplanted medial ganglionic eminence progenitors

Paterno,

Vu,

Hsieh

et al. 2024

Preprint

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Interneuron progenitor transplantation can ameliorate disease symptoms in a variety of neurological disorders. This strategy is based on transplantation of embryonic medial ganglionic eminence (MGE) progenitors. Elucidating host brain environment influences on interneuron progenitors as they integrate is critical to optimizing this strategy across different disease states. Here, we systematically evaluated age and brain region influences on survival, migration and differentiation of transplant-derived cells. We find that early postnatal MGE transplantation yields superior survival and more extensive migratory capabilities compared to juvenile or adult. MGE progenitors migrate more widely in cortex compared to hippocampus. Maturation to interneuron subtypes is regulated by age and brain region. MGE progenitors transplanted into dentate gyrus sub-region of early postnatal hippocampus can differentiate into astrocytes. Our results suggest that host brain environment critically regulates survival, spatial distribution and maturation of MGE-derived interneurons following transplantation. These findings inform and enable optimal conditions for interneuron transplant therapies.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Host brain environmental influences on transplanted medial ganglionic eminence progenitors

Paterno,

Vu,

Hsieh

et al. 2024

Preprint

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“…This targeted loss specifically in interneurons might have compromised integration into the Pcdh10- positive BLC. Previous studies have revealed a strong association between several non-clustered protocadherins and sorting defects observed both in vitro and in the developing brain, including the formation of specific aggregates due to differential δ2-protocadherin expression in vitro (81), sorting anomalies and reduced interneuron migration in the cortex of Pcdh19 mosaic females (81,83) and the mislocalization of Gad1- expressing cells in the thalamus of Pcdh10b knockdown zebrafish (97). These findings collectively suggest that loss of protocadherin expression in adjacent cells might affect their positioning and circuit integration.…”

Section: Discussionmentioning

confidence: 99%

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

Aerts,

Boonen,

Geenen

et al. 2024

Preprint

Self Cite

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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.

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“…Clinically, genetic variants in PCDH19 have been linked to a rare newly individualized syndrome: epilepsy in females with mental retardation (EFMR), also known as early infantile epileptic encephalopathy (EIEE9) or PCDH-19 clustering epilepsy (OMIM #300088), and in fact comes second in the list of genes associated with this disease [ 31 , 32 ]. This sex-limited disease is characterized by the early onset of seizures, usually with varying degrees of intellectual disability [ 33 ] and other neurobehavioral features [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

PCDH19 in Males: Are Hemizygous Variants Linked to Autism?

Chouery

Makhlouf

Khatoun

et al. 2023

Genes

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Background: Autism spectrum disorder (ASD) is a complex developmental disability that impairs the social communication and interaction of affected individuals and leads to restricted or repetitive behaviors or interests. ASD is genetically heterogeneous, with inheritable and de novo genetic variants in more than hundreds of genes contributing to the disease. However, these account for only around 20% of cases, while the molecular basis of the majority of cases remains unelucidated as of yet. Material and methods: Two unrelated Lebanese patients, a 7-year-old boy (patient A) and a 4-year-old boy (patient B), presenting with ASD were included in this study. Whole-exome sequencing (WES) was carried out for these patients to identify the molecular cause of their diseases. Results: WES analysis revealed hemizygous variants in PCDH19 (NM_001184880.1) as being the candidate causative variants: p.Arg787Leu was detected in patient A and p.Asp1024Asn in patient B. PCDH19, located on chromosome X, encodes a membrane glycoprotein belonging to the protocadherin family. Heterozygous PCDH19 variants have been linked to epilepsy in females with mental retardation (EFMR), while mosaic PCDH19 mutations in males are responsible for treatment-resistant epilepsy presenting similarly to EFMR, with some reported cases of comorbid intellectual disability and autism. Interestingly, a hemizygous PCDH19 variant affecting the same amino acid that is altered in patient A was previously reported in a male patient with ASD. Conclusion: Here, we report hemizygous PCDH19 variants in two males with autism without epilepsy. Reporting further PCDH19 variants in male patients with ASD is important to assess the possible involvement of this gene in autism.

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Modifying PCDH19 levels affects cortical interneuron migration

Cited by 12 publications

References 83 publications

Host brain environmental influences on transplanted medial ganglionic eminence progenitors

Host brain environmental influences on transplanted medial ganglionic eminence progenitors

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

PCDH19 in Males: Are Hemizygous Variants Linked to Autism?

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