Genome editing in stem cells for genetic neurodisorders

Amico, Claudia Dell'; Tata, Alice; Pellegrino, Enrica; Onorati, Marco; Conti, Luciano

doi:10.1016/bs.pmbts.2020.12.006

Cited by 7 publications

(7 citation statements)

References 132 publications

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“…We obtained NPCs from hiPSCs after cerebro-cortical induction, which recapitulates early stages of human neurodevelopment ( Figure 1 A). hiPSCs represent an extraordinary ex vivo source for the derivation of NPCs and a powerful tool to study human neurodevelopmental diseases ( Dell’ Amico et al., 2021 ). In our protocol, we generated hiPS-NPCs with a dorsal telencephalic identity, endowed with a cortical fate ( Sousa et al., 2017 ).…”

Section: Resultsmentioning

confidence: 99%

Zika virus induces FOXG1 nuclear displacement and downregulation in human neural progenitors

et al. 2022

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Section: Resultsmentioning

confidence: 99%

Zika virus induces FOXG1 nuclear displacement and downregulation in human neural progenitors

et al. 2022

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“…In this study, we investigated the impact of a C-terminal truncating mutation (D955AfsX112) in WDR62 (Sgourdou et al, 2017) on human cortical development employing patient iPSCs, which we used to derive NES cells and, through directed differentiation, mature cerebro-cortical neurons, and glia (Abdullah et al, 2017; Baggiani et al, 2020; Dell’ Amico et al, 2021). To date, human iPSC-derived NES cells and neurons have been employed in mechanistic studies of several neurodevelopmental disorders, including the CEDNIK syndrome, characterized by cerebral dysgenesis (Morelli et al, 2021), Machado–Joseph disease (spinocerebellar ataxia 3) (Koch et al, 2011), and Zika virus-induced microcephaly (Lottini et al, 2022; Onorati et al, 2016) .…”

Section: Discussionmentioning

confidence: 99%

“…We previously reported a homozygous truncating mutation (D955AfsX112) in WDR62 in patients with microcephaly and structural brain abnormalities (Sgourdou et al, 2017). In the present work, we directly investigated the effects of this mutation on NPC proliferation and neurogenic potential, taking advantage of patient-derived induced pluripotent stem cells (iPSCs) and isogenic lines generated via CRISPR/Cas9 gene editing (Dell’ Amico et al, 2021). From WDR62 and Isogenic iPSCs we derived neuroepithelial stem (NES) cells, the founders of cerebro-cortical cellular complexity (Baggiani et al, 2020; Onorati et al, 2016), as well as terminally differentiated cerebro-cortical neurons, through a directed differentiation protocol (Chambers et al, 2009; Shi et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Microcephaly-associated WDR62 mutations hamper Golgi apparatus-to-spindle pole shuttling in human neural progenitors

Dell’Amico

Salavarria

Takeo

et al. 2022

Preprint

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WDR62 is a spindle pole-associated scaffold protein with pleiotropic functions during corticogenesis. Recessive mutations in WDR62 are associated with structural brain abnormalities and account for the second most common cause of autosomal recessive primary microcephaly (MCPH), indicating WDR62 as a critical hub for human brain development. Here, we investigated a C-terminal truncating mutation (D955AfsX112) in WDR62 using induced pluripotent stem cells (iPSCs) obtained from a patient with MCPH2. We generated neuroepithelial stem (NES) cells and cerebro-cortical progenitors and neurons from patient-derived and isogenic retro-mutated iPSC lines. We found that WDR62 dysfunction resulted in impaired cell cycle progression and alterations of the neurogenic trajectories of iPSC neuroderivatives. Moreover, we report WDR62 localization at the Golgi apparatus during interphase, both in human neural progenitors in vitro and in human fetal brain tissue. WDR62 shuttling from the Golgi apparatus to spindle poles is dynamic and microtubule-dependent. Impairment of WDR62 function and localization results in severe neurodevelopmental abnormalities, thus delineating new mechanisms in MCPH etiology.

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“…Nowadays, 2D and 3D neural cultures derived from human pluripotent stem cells (hiPSCs) (Dell'Amico et al, 2021) provide a key tool to comprehend the complex CT networks. Moreover, Different approaches to study CT-TC network.…”

Section: Shifting Borders-exploring Cortico-thalamic Development Thro...mentioning

confidence: 99%

Cortico-thalamic development and disease: From cells, to circuits, to schizophrenia

Salavarria

Dell’Amico²,

D’Agostino³

et al. 2023

Front. Neuroanat.

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The human brain is the most complex structure generated during development. Unveiling the ontogenesis and the intrinsic organization of specific neural networks may represent a key to understanding the physio-pathological aspects of different brain areas. The cortico-thalamic and thalamo-cortical (CT-TC) circuits process and modulate essential tasks such as wakefulness, sleep and memory, and their alterations may result in neurodevelopmental and psychiatric disorders. These pathologies are reported to affect specific neural populations but may also broadly alter physiological connections and thus dysregulate brain network generation, communication, and function. More specifically, the CT-TC system is reported to be severely affected in disorders impacting superior brain functions, such as schizophrenia (SCZ), bipolar disorder, autism spectrum disorders or epilepsy. In this review, the focus will be on CT development, and the models exploited to uncover and comprehend its molecular and cellular mechanisms. In parallel to animal models, still fundamental to unveil human neural network establishment, advanced in vitro platforms, such as brain organoids derived from human pluripotent stem cells, will be discussed. Indeed, organoids and assembloids represent unique tools to study and accelerate fundamental research in CT development and its dysfunctions. We will then discuss recent cutting-edge contributions, including in silico approaches, concerning ontogenesis, specification, and function of the CT-TC circuitry that generates connectivity maps in physiological and pathological conditions.

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Genome editing in stem cells for genetic neurodisorders

Cited by 7 publications

References 132 publications

Zika virus induces FOXG1 nuclear displacement and downregulation in human neural progenitors

Zika virus induces FOXG1 nuclear displacement and downregulation in human neural progenitors

Microcephaly-associated WDR62 mutations hamper Golgi apparatus-to-spindle pole shuttling in human neural progenitors

Cortico-thalamic development and disease: From cells, to circuits, to schizophrenia

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