Biology subjects

Meganathan, K.

Publications and source records attributed to Meganathan, K..

3 recordsLinked to original sources

bioRxiv2024

Autism and Intellectual Disability-Associated MYT1L Mutation Alters Human Cortical Interneuron Differentiation, Maturation, and Physiology

MYT1L is a neuronal transcription factor highly expressed in the developing and adult brain. While pathogenic MYT1L mutation causes neurodevelopmental disorders, these have not been characterized in human models of neurodevelopment. Here, we defined the consequences of pathogenic MYT1L mutation in human pluripotent stem cell-derived cortical interneurons. During differentiation, mutation reduced MYT1L expression and increased progenitor cell cycle exit and neuronal differentiation and synapse-related gene expression, morphological complexity, and synaptic puncta formation. Conversely, interneuron maturation was compromised, while variant neurons exhibited altered sodium and potassium channel activity and reduced function in electrophysiological analyses. CRISPRi-based knockdown similarly impaired interneuron differentiation and maturation, supporting loss of function-based effects. We further defined MYT1L genome-wide occupancy in interneurons and related this to the transcriptomic dysregulation resulting from MYT1L mutation, to identify direct targets that could mediate these phenotypic consequences. Together, this work delineates contributors to the etiology of neurodevelopmental disorders resulting from MYT1L mutation.

developmental biology↗

bioRxiv2020

Alterations in neuronal physiology, development, and function associated with a common duplication of chromosome 15 involving CHRNA7

BackgroundCopy number variants at chromosome 15q13.3 contribute to liability for multiple intellectual and developmental disabilities including Autism Spectrum Disorder (ASD). Individuals with duplications of this interval, which includes the gene CHRNA7, have multiple psychiatric disorders with widely variable penetrance. However, the basis of such differential affectation remains uncharacterized. MethodsInduced pluripotent stem cell (iPSC) models were generated from two first degree relatives with the same 15q13.3 duplication, a boy with distinct features of autism and emotional dysregulation (the affected proband, AP) and his clinically unaffected mother (the UM). These models were compared to unrelated control subjects lacking this duplication (UC, male and female). iPSC-derived neural progenitors and cortical neuroids consisting of cortical excitatory and inhibitory neurons were used to model potential contributors to neuropsychiatric impairment. ResultsThe AP-derived model uniquely exhibited disruptions of cellular physiology and neurodevelopment not observed in either the UM or the unrelated male and female controls. These included enhanced neural progenitor proliferation but impaired neuronal differentiation, maturation, and migration, and increased endoplasmic reticulum (ER) stress. Both the AP models neuronal migration deficit and elevated ER stress could be selectively rescued by different pharmacologic agents. Neuronal gene expression was also specifically dysregulated in the AP, including reduced expression of genes related to behavior, psychological disorders, neuritogenesis, neuronal migration, and WNT, axonal guidance, and GABA receptor signaling. Interestingly, the UM model exhibited upregulated expression of genes in many of these same pathways, by comparison with both the AP and UC models, suggesting that cell intrinsic molecular compensation could have contributed to the lack of neurodevelopmental phenotypes in the UM model. However, by contrast with the AP-specific neurodevelopmental phenotypes, both the AP- and UM-derived neurons exhibited shared alterations of neuronal function, including increased action potential firing and elevated cholinergic activity, consistent with increased homomeric CHRNA7 channel activity. ConclusionTogether, these data define both affectation-specific phenotypes seen only in the AP, as well as abnormalities observed in both individuals with CHRNA7 duplication, the AP and UM, but not in UC-derived neurons. This is, to our knowledge, the first study to use a human stem cell-based platform to study the basis of variable affectation in cases of 15q13.3 duplication at the cellular, molecular, and functional levels. This work suggests potential approaches for suppressing abnormal neurodevelopment or physiology that may contribute to severity of affectation. Some of these AP-specific neurodevelopmental anomalies, or the functional anomalies observed in both 15q13.3 duplication carriers (the AP and UM), could also contribute to the variable phenotypic penetrance seen in other individuals with 15q13.3 duplication.

developmental biology↗

bioRxiv2019

Cellular and molecular characterization of multiplex autism in human induced pluripotent stem cell-derived neurons

BackgroundAutism spectrum disorder (ASD) is a neurodevelopmental disorder with pronounced heritability in the general population. This is largely attributable to effects of polygenic susceptibility, with inherited liability exhibiting distinct sex differences in phenotypic expression. Attempts to model ASD in human cellular systems have principally involved rare de novo mutations associated with ASD phenocopies. However, by definition, these models are not representative of polygenic liability, which accounts for the vast share of population-attributable risk.\n\nMethodsHere, we performed what is, to our knowledge, the first attempt to model multiplex autism using patient-derived induced pluripotent stem cells (iPSCs) in a family manifesting incremental degrees of phenotypic expression of inherited liability (absent, intermediate, severe). The family members share an inherited variant of unknown significance in GPD2, a gene that was previously associated with developmental disability but here is insufficient by itself to cause ASD. iPSCs from three first-degree relatives and an unrelated control were differentiated into both cortical excitatory (cExN) and cortical inhibitory (cIN) neurons, and cellular phenotyping and transcriptomic analysis were conducted.\n\nResultscExN neurospheres from the two affected individuals were reduced in size, compared to those derived from unaffected related and unrelated individuals. This reduction was, at least in part, due to increased apoptosis of cells from affected individuals upon initiation of cExN neural induction. Likewise, cIN neural progenitor cells from affected individuals exhibited increased apoptosis, compared to both unaffected individuals. Transcriptomic analysis of both cExN and cIN neural progenitor cells revealed distinct molecular signatures associated with affectation, including misregulation of suites of genes associated with neural development, neuronal function, and behavior, as well as altered expression of ASD risk-associated genes.\n\nConclusionsWe have provided evidence of morphological, physiological, and transcriptomic signatures of polygenic liability to ASD from an analysis of cellular models derived from a multiplex autism family. ASD is commonly inherited on the basis of additive genetic liability. Therefore, identifying convergent cellular and molecular phenotypes resulting from polygenic and monogenic susceptibility may provide a critical bridge for determining which of the disparate effects of rare highly deleterious mutations might also apply to common autistic syndromes.

neuroscience↗