Nf1deletion results in depletion of theLhx6transcription factor and a specific loss of parvalbumin+cortical interneurons

Angara, Kartik; Pai, Emily Ling Lin; Bilinovich, Stephanie M.; Stafford, April M; Nguyen, Julie T.; Li, Katie X.; Paul, Anirban; Rubenstein, John L.R.; Vogt, Daniel

doi:10.1073/pnas.1915458117

Cited by 26 publications

(41 citation statements)

References 56 publications

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“…We next examined the expression of SST in the transplanted cells. In agreement with our previous studies, the proportion of Nf1 cKO cells that expressed SST was similar to WTs (Figure 1I) (Angara et al, 2020;Holter et al, 2021). In contrast, most of the Braf ca cells expressed SST at high levels (Figure 1I; WT and Nf1 cKO vs. Braf ca p < 0.0001).…”

Section: Nf1 and Braf Ca Mutants Exhibit Similar Decreases In Pv But ...supporting

confidence: 91%

“…Overall, each mutant exhibited alterations in CIN markers with the more pronounced phenotypes observed in bRaf ca mutants. While LHX6 expression was also decreased in Nf1 conditional heterozygous (cHet) cells, SST or PV levels were not changed (Angara et al, 2020), suggesting other potential mechanisms underlying SST and PV phenotypes.…”

Section: Nf1 and Braf Ca Mutants Exhibit Similar Decreases In Pv But ...mentioning

confidence: 99%

“…Earlier studies examining the RAS/MAPK pathway inhibitor, Nf1, suggested that GABAergic dysfunction could be a key factor in the cognitive changes associated with RAS/MAPK disorders (Costa et al, 2002;Cui et al, 2008). More recent studies identified specific cellular and molecular consequences of RAS/MAPK hyperactivation in GABAergic cortical interneurons (CINs), including the loss of parvalbumin (PV)+ CINs and a decrease in LHX6 (Angara et al, 2020;Holter et al, 2021;Omrani et al, 2015). LHX6 is a cardinal transcription factor that is necessary for the emergence of CIN populations from the medial ganglionic eminence (MGE) (Liodis et al, 2007;Vogt et al, 2014;Zhao et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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Distinct hyperactive RAS/MAPK alleles converge on common GABAergic interneuron core programs

Knowles

Stafford

Zaman

et al. 2022

Preprint

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RAS/MAPK gene dysfunction underlies various cancers and neurocognitive disorders. While the role of RAS/MAPK genes have been well studied in cancer, less is known about their function during neurodevelopment. There are many genes that work in concert to regulate RAS/MAPK signaling, suggesting that if common brain phenotypes could be discovered they could have a broad impact on the many other disorders caused by distinct RAS/MAPK genes. We assessed the cellular and molecular consequences of hyperactivating the RAS/MAPK pathway using three distinct genes in a cell type previously implicated in RAS/MAPK-mediated cognitive changes, cortical GABAergic interneurons. We uncovered a spectrum of GABAergic core programs that are commonly altered in each of the mutants. Notably, hyperactive RAS/MAPK mutants bias developing cortical interneurons towards those that are somatostatin+. The increase in somatostatin+ interneurons could also be induced by elevated neural activity and we show the core RAS/MAPK signaling pathway is one mechanism by which this occurs. Overall, these findings present new insights into how different RAS/MAPK mutations can converge on GABAergic interneurons, which may be important for other RAS/MAPK genes/disorders.

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Section: Nf1 and Braf Ca Mutants Exhibit Similar Decreases In Pv But ...supporting

confidence: 91%

Section: Nf1 and Braf Ca Mutants Exhibit Similar Decreases In Pv But ...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Distinct hyperactive RAS/MAPK alleles converge on common GABAergic interneuron core programs

Knowles

Stafford

Zaman

et al. 2022

Preprint

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“…We performed MGE primary cultures as described in Angara et al (2020). Briefly, we cultured MGE cells in DMEM supplemented with 10% FBS and penicillin/streptomycin from time of seeding until 1 day in vitro.…”

Section: Mge Primary Culturesmentioning

confidence: 99%

“…CIN dysfunction is implicated in ASD and altered in both humans diagnosed with ASD and in ASD genetic deletion models (Vogt et al, 2015a(Vogt et al, , 2018Hoffman et al, 2016;Hashemi et al, 2017;Jung et al, 2017;Soghomonian et al, 2017;Pla et al, 2018;Elbert et al, 2019;Malik et al, 2019;Angara et al, 2020). CINs are derived from the medial and caudal ganglionic eminences (MGE and CGE), as well as the preoptic area (Wonders and Anderson, 2006;Gelman et al, 2011;Hu et al, 2017b).…”

Section: Introductionmentioning

confidence: 99%

A Human TSC1 Variant Screening Platform in Gabaergic Cortical Interneurons for Genotype to Phenotype Assessments

Wundrach

Martinetti

Stafford

et al. 2020

Front. Mol. Neurosci.

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The TSC1 and TSC2 genes are connected to multiple syndromes from Tuberous Sclerosis Complex (TSC) to autism spectrum disorder (ASD), with uncertainty if genetic variants cause all or subsets of phenotypes based on the location and type of change. For TSC1, few have addressed if non-TSC associated genetic variants have direct contributions to changes in neurological genotype-to-phenotype impacts, including elevated rates of ASD and seizures. Dominant variants cause TSC, yet TSC1 has many heritable variants not dominant for TSC that are poorly understood in neurological function, with some associated with ASD. Herein, we examined how missense variants in TSC1, R336W, T360N, T393I, S403L, and H732Y, impacted the development of cortical inhibitory interneurons, cell-types whose molecular, cellular, and physiological properties are altered after the loss of mouse TSC1. We found these variants complemented a known phenotype caused by loss of TSC1, increased cell size. However, distinct variants, particularly S403L showed deficits in complementing an increase in parvalbumin levels and exhibited smaller amplitude after hyperpolarizations. Overall, these data show that subtle phenotypes can be induced by some TSC1 missense variants and provide an in vivo system to assess TSC1 variants' neurological impact better.

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A new era for myelin research in Neurofibromatosis type 1

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Nishiyama

López‐Juárez

2023

Glia

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Evidence for myelin regulating higher‐order brain function and disease is rapidly accumulating; however, defining cellular/molecular mechanisms remains challenging partially due to the dynamic brain physiology involving deep changes during development, aging, and in response to learning and disease. Furthermore, as the etiology of most neurological conditions remains obscure, most research models focus on mimicking symptoms, which limits understanding of their molecular onset and progression. Studying diseases caused by single gene mutations represents an opportunity to understand brain dys/function, including those regulated by myelin. Here, we discuss known and potential repercussions of abnormal central myelin on the neuropathophysiology of Neurofibromatosis Type 1 (NF1). Most patients with this monogenic disease present with neurological symptoms diverse in kind, severity, and onset/decline, including learning disabilities, autism spectrum disorders, attention deficit and hyperactivity disorder, motor coordination issues, and increased risk for depression and dementia. Coincidentally, most NF1 patients show diverse white matter/myelin abnormalities. Although myelin‐behavior links were proposed decades ago, no solid data can prove or refute this idea yet. A recent upsurge in myelin biology understanding and research/therapeutic tools provides opportunities to address this debate. As precision medicine moves forward, an integrative understanding of all cell types disrupted in neurological conditions becomes a priority. Hence, this review aims to serve as a bridge between fundamental cellular/molecular myelin biology and clinical research in NF1.

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Nf1deletion results in depletion of theLhx6transcription factor and a specific loss of parvalbumin⁺cortical interneurons

Cited by 26 publications

References 56 publications

Distinct hyperactive RAS/MAPK alleles converge on common GABAergic interneuron core programs

Distinct hyperactive RAS/MAPK alleles converge on common GABAergic interneuron core programs

A Human TSC1 Variant Screening Platform in Gabaergic Cortical Interneurons for Genotype to Phenotype Assessments

A new era for myelin research in Neurofibromatosis type 1

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