scholarly journals JIP2 haploinsufficiency contributes to neurodevelopmental abnormalities in human pluripotent stem cell-derived neural progenitors and cortical neurons

2017 ◽  
Author(s):  
Reinhard Roessler ◽  
Johanna Goldmann ◽  
Chikdu Shivalila ◽  
Rudolf Jaenisch
Keyword(s):  
Stem Cell ◽  
Cortical Neurons ◽  
Pluripotent Stem Cell ◽  
Autism Spectrum ◽  
Neural Progenitors ◽  
Deletion Syndrome ◽  
Human Pluripotent Stem Cell ◽  
Cellular Mechanisms ◽  
Mature Neurons ◽  
Neurodevelopmental Abnormalities

AbstractPhelan-McDermid syndrome (also known as 22q13 deletion syndrome) is a syndromic form of autism spectrum disorder and currently thought to be caused by heterozygous loss of SHANK3. However, patients most frequently present with large chromosomal deletions affecting several additional genes. We used human pluripotent stem cell technology and genome editing to further dissect molecular and cellular mechanisms. We found that loss of JIP2 (MAPK8IP2) may contribute to a distinct neurodevelopmental phenotype in neural progenitors (NPCs) affecting neuronal maturation. This is most likely due to simultaneous misregulation of JNK proteins, leading to impaired generation of mature neurons. Furthermore, semaphorin signaling is compromised in patient NPCs and neurons. Pharmacological stimulation of neuropilin receptor 1 (NRP1) rescued impaired semaphorin pathway activity and JNK expression in patient neurons. Our results suggest a novel disease-specific mechanism involving the JIP/JNK complex and identify NRP1 as potential therapeutic target.

scholarly journals JIP2 haploinsufficiency contributes to neurodevelopmental abnormalities in human pluripotent stem cell–derived neural progenitors and cortical neurons

2018 ◽  
Vol 1 (4) ◽  
pp. e201800094 ◽  
Author(s):  
Reinhard Roessler ◽  
Johanna Goldmann ◽  
Chikdu Shivalila ◽  
Rudolf Jaenisch
Keyword(s):  
Stem Cell ◽  
Cortical Neurons ◽  
Pluripotent Stem Cell ◽  
Neural Progenitor Cells ◽  
Autism Spectrum ◽  
Deletion Syndrome ◽  
Human Pluripotent Stem Cell ◽  
Cellular Mechanisms ◽  
Mature Neurons ◽  
Neurodevelopmental Abnormalities

Phelan–McDermid syndrome (also known as 22q13.3 deletion syndrome) is a syndromic form of autism spectrum disorder and currently thought to be caused by heterozygous loss of SHANK3. However, patients most frequently present with large chromosomal deletions affecting several additional genes. We used human pluripotent stem cell technology and genome editing to further dissect molecular and cellular mechanisms. We found that loss of JIP2 (MAPK8IP2) may contribute to a distinct neurodevelopmental phenotype in neural progenitor cells (NPCs) affecting neuronal maturation. This is most likely due to a simultaneous down-regulation of c-Jun N-terminal kinase (JNK) proteins, leading to impaired generation of mature neurons. Furthermore, semaphorin signaling appears to be impaired in patient NPCs and neurons. Pharmacological activation of neuropilin receptor 1 (NRP1) rescued impaired semaphorin pathway activity and JNK expression in patient neurons. Our results suggest a novel disease-specific mechanism involving the JIP/JNK complex and identify NRP1 as a potential new therapeutic target.

scholarly journals Mitochondrial gene replacement in human pluripotent stem cell-derived neural progenitors

Gene Therapy ◽  
2011 ◽  
Vol 19 (5) ◽  
pp. 469-475 ◽  
Author(s):  
S Iyer ◽  
E Xiao ◽  
K Alsayegh ◽  
N Eroshenko ◽  
M J Riggs ◽  
...  
Keyword(s):  
Stem Cell ◽  
Pluripotent Stem Cell ◽  
Mitochondrial Gene ◽  
Gene Replacement ◽  
Neural Progenitors ◽  
Human Pluripotent Stem Cell

scholarly journals Human Pluripotent Stem Cell-derived Cortical Neurons for High Throughput Medication Screening in Autism: A Proof of Concept Study in SHANK3 Haploinsufficiency Syndrome

EBioMedicine ◽  
2016 ◽  
Vol 9 ◽  
pp. 293-305 ◽  
Author(s):  
Hélène Darville ◽  
Aurélie Poulet ◽  
Frédérique Rodet-Amsellem ◽  
Laure Chatrousse ◽  
Julie Pernelle ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Throughput ◽  
Cortical Neurons ◽  
Pluripotent Stem Cell ◽  
Proof Of Concept ◽  
Human Pluripotent Stem Cell ◽  
Concept Study ◽  
Medication Screening

scholarly journals Synaptic dysfunction in neurodegenerative and neurodevelopmental diseases: an overview of induced pluripotent stem-cell-based disease models

Open Biology ◽  
2018 ◽  
Vol 8 (9) ◽  
pp. 180138 ◽  
Author(s):  
Era Taoufik ◽  
Georgia Kouroupi ◽  
Ourania Zygogianni ◽  
Rebecca Matsas
Keyword(s):  
Stem Cell ◽  
Neurodegenerative Diseases ◽  
Pluripotent Stem Cell ◽  
Clinical Symptoms ◽  
Induced Pluripotent Stem Cell ◽  
Autism Spectrum ◽  
Synaptic Dysfunction ◽  
Disease Models ◽  
Cellular Mechanisms ◽  
Induced Pluripotent

Synaptic dysfunction in CNS disorders is the outcome of perturbations in physiological synapse structure and function, and can be either the cause or the consequence in specific pathologies. Accumulating data in the field of neuropsychiatric disorders, including autism spectrum disorders, schizophrenia and bipolar disorder, point to a neurodevelopmental origin of these pathologies. Due to a relatively early onset of behavioural and cognitive symptoms, it is generally acknowledged that mental illness initiates at the synapse level. On the other hand, synaptic dysfunction has been considered as an endpoint incident in neurodegenerative diseases, such as Alzheimer's, Parkinson's and Huntington's, mainly due to the considerably later onset of clinical symptoms and progressive appearance of cognitive deficits. This dichotomy has recently been challenged, particularly since the discovery of cell reprogramming technologies and the generation of induced pluripotent stem cells from patient somatic cells. The creation of ‘disease-in-a-dish’ models for multiple CNS pathologies has revealed unexpected commonalities in the molecular and cellular mechanisms operating in both developmental and degenerative conditions, most of which meet at the synapse level. In this review we discuss synaptic dysfunction in prototype neurodevelopmental and neurodegenerative diseases, emphasizing overlapping features of synaptopathy that have been suggested by studies using induced pluripotent stem-cell-based systems. These valuable disease models have highlighted a potential neurodevelopmental component in classical neurodegenerative diseases that is worth pursuing and investigating further. Moving from demonstration of correlation to understanding mechanistic causality forms the basis for developing novel therapeutics.

scholarly journals Human Pluripotent Stem-Cell-Derived Cortical Neurons Integrate Functionally into the Lesioned Adult Murine Visual Cortex in an Area-Specific Way

Cell Reports ◽  
2018 ◽  
Vol 23 (9) ◽  
pp. 2732-2743 ◽  
Author(s):  
Ira Espuny-Camacho ◽  
Kimmo A. Michelsen ◽  
Daniele Linaro ◽  
Angéline Bilheu ◽  
Sandra Acosta-Verdugo ◽  
...  
Keyword(s):  
Stem Cell ◽  
Visual Cortex ◽  
Cortical Neurons ◽  
Pluripotent Stem Cell ◽  
Human Pluripotent Stem Cell
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