Show simple item record

Deciphering the functional role of the LIS1/NDEL1/14.3.3ε protein complex in the expansion of human cortical progenitors in an iPSC-derived organoid model

dc.contributor.advisorBrüstle, Oliver
dc.contributor.authorIefremova, Vira
dc.date.accessioned2021-07-19T15:11:19Z
dc.date.available2021-07-19T15:11:19Z
dc.date.issued19.07.2021
dc.identifier.urihttps://hdl.handle.net/20.500.11811/9230
dc.description.abstractThe human brain is an exceptionally complex organ, both structurally and functionally, and represents the most remarkable progress in evolution. The human cortex is a highly organised and extensively folded structure consisting of radially organised layers: gyri and sulci. For many years, transgenic mouse models were used to study gene function in the developing cortex. Recently, it was suggested that human brain development could also be modelled in vitro using the capacity of pluripotent stem cells (PSCs) to self-organise into so-called brain organoids. They contain different cell types that organise in a spatially similar way to the developing human brain and accurately recapitulate developmental gene expression patterns. This study focuses on investigating the functional role of the LIS1 gene during human cortical development. LIS1 and its interactive partners, NDEL1 and 14.3.3e, have been cited as crucial for neuronal migration and cortical layer formation and were recently demonstrated to have a role in the expansion of cortical progenitors. Moreover, heterozygous deletions or mutations in LIS1 constitute the most common cause of lissencephaly. We established a standardised induced PSC-derived cortical organoid model to decipher the functional role of the LIS1/NDEL1/14.3.3e protein complex during human cortical development. To that end, we reprogrammed fibroblasts from patients suffering from haploinsufficiency of chromosome 17p13.3, which involves the genes encoding LIS1 and 14.3.3e, and differentiate them into cortical cultures. We analysed proliferation and neurogenesis on morphological, biochemical, and molecular levels, and demonstrated that patientderived organoids show a significant size reduction, resulting from a shift in ventricular zone radial glial cells from symmetric to asymmetric mode of cell division. This was associated with alterations in microtubule networks and the disruption of cortical niche architecture, leading to a non-cell-autonomous disturbance in the Ncadherin/ß-catenin signalling axis. Reinstallation of β-catenin signalling resulted in a return to symmetric cell division and rescued growth deficits. We provided a novel experimental model to analyse the functional roles of LIS1 and 14.3.3e during human cortical progenitor expansion. Significantly, our data highlights a new role for these proteins in maintaining the cortical niche and suggests that organoids may serve as a useful model for assessing aspects of early cortical development, such as progenitor cell proliferation, cell cycle dynamics, and neurogenesis.en
dc.language.isoeng
dc.rightsIn Copyright
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/
dc.subject.ddc570 Biowissenschaften, Biologie
dc.subject.ddc610 Medizin, Gesundheit
dc.titleDeciphering the functional role of the LIS1/NDEL1/14.3.3ε protein complex in the expansion of human cortical progenitors in an iPSC-derived organoid model
dc.typeDissertation oder Habilitation
dc.publisher.nameUniversitäts- und Landesbibliothek Bonn
dc.publisher.locationBonn
dc.rights.accessRightsopenAccess
dc.identifier.urnhttps://nbn-resolving.org/urn:nbn:de:hbz:5-62915
ulbbn.pubtypeErstveröffentlichung
ulbbnediss.affiliation.nameRheinische Friedrich-Wilhelms-Universität Bonn
ulbbnediss.affiliation.locationBonn
ulbbnediss.thesis.levelDissertation
ulbbnediss.dissID6291
ulbbnediss.date.accepted24.06.2021
ulbbnediss.instituteMedizinische Fakultät / Institute : Institut für Rekonstruktive Neurobiologie (IRN)
ulbbnediss.fakultaetMathematisch-Naturwissenschaftliche Fakultät
dc.contributor.coRefereePankratz, Michael
ulbbn.doiRequestnein


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record

The following license files are associated with this item:

InCopyright