In addition, we provide evidence that subdomains of PCDH19 have a different impact on cell survival and interneuron migration. We confirm this finding in vivo by showing a mild reduction in interneuron migration in heterozygote, but not in homozygote PCDH19 knockout animals. We also detect subtle defects when PCDH19 expression was reduced in MGE explants, suggesting that the dosage of PCDH19 is important for proper interneuron migration. We show that cortical interneuron migration is affected by altering PCDH19 dosage by means of overexpression in brain slices and medial ganglionic eminence (MGE) explants. As epilepsy can also be caused by impaired interneuron migration, we studied the role of PCDH19 in cortical interneurons during embryogenesis. Several studies have shown roles for PCDH19 in neuronal proliferation, migration, and synapse function, yet most of them have focused on cortical and hippocampal neurons. A disturbed cell-cell contact that arises when random X-inactivation creates mosaic absence of PCDH19 has been proposed to cause the syndrome. It is encoded by the X-chromosome and more than 200 mutations have been linked to the neurodevelopmental PCDH-clustering epilepsy (PCDH19-CE) syndrome. PCDH19 is a transmembrane protein and member of the protocadherin family. Unraveling this neurodegenerative cascade provides a new paradigm to interrogate FTLD pathogenesis. Our study suggests that TDP-43 acetylation drives neuronal dysfunction and cognitive decline through aberrant splicing and transcription of critical genes, many of which modulate synaptic plasticity and stress response signaling. Mice harboring the TDP-43 K145Q mutation recapitulate key hallmarks of FTLD-TDP, including progressive TDP-43 phosphorylation and insolubility, mis-localization, transcriptomic and splicing alterations, and cognitive dysfunction. Expression of acetylation-mimic TDP-43 K145Q resulted in stress-induced phase-separated TDP-43 foci and loss-of-TDP-43-function in mouse primary neurons and human induced pluripotent stem cell-derived neurons. Here, we developed an endogenous model of sporadic TDP-43 proteinopathy based on the principle that disease-associated TDP-43 acetylation at lysine 145 (K145) alters TDP-43 conformation, impairs RNA-binding capacity, and induces downstream mis-regulation of target genes. TDP-43 proteinopathies including frontotemporal lobar dementia (FTLD) and amyotrophic lateral sclerosis are neurodegenerative disorders characterized by aggregation and mislocalization of TDP-43 and subsequent neuronal dysfunction. This release will ensure that researchers will have continued access to CellProfiler’s powerful computational tools in the coming years. We also evaluated performance and made targeted optimizations to reduce the time and cost associated with running common large-scale analysis pipelines.ĬellProfiler 4 provides significantly improved performance in complex workflows compared to previous versions. We introduced new modules to expand the capabilities of the software. Based on user feedback, we have made several user interface refinements to improve the usability of the software. #CELLPROFILER MAC INSTALATION SOFTWARE#Herein we describe CellProfiler 4, a new version of this software with expanded functionality. CellProfiler is a free, open source image analysis program which enables researchers to generate modular pipelines with which to process microscopy images into interpretable measurements. With the expansion of high throughput microscopy methodologies producing increasingly large datasets, automated and objective analysis of the resulting images is essential to effectively extract biological information from this data. Imaging data contains a substantial amount of information which can be difficult to evaluate by eye.
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