The use of brain organoids to investigate neural development and disease

Lullo, Elizabeth Di; Kriegstein, Arnold R.

doi:10.1038/nrn.2017.107

Cited by 590 publications

(529 citation statements)

References 91 publications

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“…This could be due to the largely absent bRG population in the developing mouse neocortex. It may be useful to utilize in vitro models of human cortical development such as human cerebral organoids formed from patient-derived induced pluripotent stem (IPS) cells [95]. Furthermore, whether variations in Shh signaling activity during corticogenesis affect maturation and connectivity of upper layer PNs produced by IPs and bRGs should be investigated.…”

Section: Implications Of Shh Signaling In Neurological Disordersmentioning

confidence: 99%

Sonic Hedgehog Signaling Rises to the Surface: Emerging Roles in Neocortical Development

Yabut

Pleasure

2018

BPL

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The mammalian neocortex is composed of a diverse population of neuronal and glial cells that are crucial for cognition and consciousness. Orchestration of molecular events that lead to the production of distinct cell lineages is now a major research focus. Recent studies in mammalian animal models reveal that Sonic Hedgehog (Shh) signaling plays crucial roles in this process. In this review, we will evaluate these studies and provide insights on how Shh signaling specifically influence cortical development, beyond its established roles in telencephalic patterning, by specifically focusing on its impact on cells derived from the cortical radial glial (RG) cells. We will also assess how these findings further advance our knowledge of neurological diseases and discuss potential roles of targeting Shh signaling in therapies.

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Section: Implications Of Shh Signaling In Neurological Disordersmentioning

confidence: 99%

Sonic Hedgehog Signaling Rises to the Surface: Emerging Roles in Neocortical Development

Yabut

Pleasure

2018

BPL

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“…The small effect sizes may still be a problem, but others and we have shown that when one works with modified or edited cells, small effect variants can lead to robust cellular phenotypes [103, 105, 139, 176]. These technologies are new, and there is still much space for improvement, including editing efficiency [177], uniform and specific differentiation [178, 179], the time needed for maturation, and the faithful recapitulation of cortical circuits by organoids [180]. Nevertheless, the genetic findings are there and the tools for us to understand them are rapidly evolving, giving hope for significant breakthroughs within the next decade.…”

Section: Closing Remarksmentioning

confidence: 99%

Recent Advances in the Genetics of Schizophrenia

Avramopoulos

2018

Complex Psychiatry

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The last decade brought tremendous progress in the field of schizophrenia genetics. As a result of extensive collaborations and multiple technological advances, we now recognize many types of genetic variants that increase the risk. These include large copy number variants, rare coding inherited and de novο variants, and over 100 loci harboring common risk variants. While the type and contribution to the risk vary among genetic variants, there is concordance in the functions of genes they implicate, such as those whose RNA binds the fragile X-related protein FMRP and members of the activity-regulated cytoskeletal complex involved in learning and memory. Gene expression studies add important information on the biology of the disease and recapitulate the same functional gene groups. Studies of alternative phenotypes help us widen our understanding of the genetic architecture of mental function and dysfunction, how diseases overlap not only with each other but also with non-disease phenotypes. The challenge is to apply this new knowledge to prevention and treatment and help patients. The data generated so far and emerging technologies, including new methods in cell engineering, offer significant promise that in the next decade we will unlock the translational potential of these significant discoveries.

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“…They allow interpretation of whether genetic variants associated with neuropsychiatric illness are also associated with the structure or function of the human brain within specific regions. Finally, directed stem cell differentiation protocols producing specific cell types from multiple brain regions and modern genetic engineering techniques allow the experimental validation of predicted causal pathways in a controlled human system . This review seeks to place maps of genetic variation associated with gross brain structure into context and explain their utility for describing causal pathways impacting risk for neuropsychiatric disorders.…”

Section: The Role That Human Neuroimaging Of Gross Brain Structure Camentioning

confidence: 99%

Mapping causal pathways from genetics to neuropsychiatric disorders using genome‐wide imaging genetics: Current status and future directions

Stein

2019

Psychiatry Clin Neurosci

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Imaging genetics aims to identify genetic variants associated with the structure and function of the human brain. Recently, collaborative consortia have been successful in this goal, identifying and replicating common genetic variants influencing gross human brain structure as measured through magnetic resonance imaging. In this review, we contextualize imaging genetic associations as one important link in understanding the causal chain from genetic variant to increased risk for neuropsychiatric disorders. We provide examples in other fields of how identifying genetic variant associations to disease and multiple phenotypes along the causal chain has revealed a mechanistic understanding of disease risk, with implications for how imaging genetics can be similarly applied. We discuss current findings in the imaging genetics research domain, including that common genetic variants can have a slightly larger effect on brain structure than on risk for disorders like schizophrenia, indicating a somewhat simpler genetic architecture. Also, gross brain structure measurements share a genetic basis with some, but not all, neuropsychiatric disorders, invalidating the previously held belief that they are broad endophenotypes, yet pinpointing brain regions likely involved in the pathology of specific disorders. Finally, we suggest that in order to build a more detailed mechanistic understanding of the effects of genetic variants on the brain, future directions in imaging genetics research will require observations of cellular and synaptic structure in specific brain regions beyond the resolution of magnetic resonance imaging. We expect that integrating genetic associations at biological levels from synapse to sulcus will reveal specific causal pathways impacting risk for neuropsychiatric disorders.

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The use of brain organoids to investigate neural development and disease

Cited by 590 publications

References 91 publications

Sonic Hedgehog Signaling Rises to the Surface: Emerging Roles in Neocortical Development

Sonic Hedgehog Signaling Rises to the Surface: Emerging Roles in Neocortical Development

Recent Advances in the Genetics of Schizophrenia

Mapping causal pathways from genetics to neuropsychiatric disorders using genome‐wide imaging genetics: Current status and future directions

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