Molecular mechanisms underlying cortical (mal)formation: case studies of ESCO2 and EXOSC10

by Pauline Ulmke
Cumulative thesis
Date of Examination:2021-08-23
Date of issue:2021-09-23
Advisor:Prof. Dr. Jochen Staiger
Referee:Dr. Sebastian Kügler
Referee:Prof. Dr. André Fischer
Referee:Prof. Dr. Ralf Heinrich
Referee:Prof. Dr. Tiago Fleming Outeiro
Referee:Prof. Dr. Bernd Wollnik
Persistent Address: http://dx.doi.org/10.53846/goediss-8819

 

 

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Abstract

English

This work focuses on elucidating the molecular mechanisms that control the cortical development. Identification of genes and factors that direct the development of the cerebral cortex will both tell us about their disease-related importance and improve our understanding of the normal formation and malformation of the cortex. In the first part, we performed transcriptome analysis to determine the molecular profile of IPCs, which play a crucial role in cortical formation as they generate the majority of cortical neurons. Accordingly, we sorted TBR2+ IPCs from the embryonic mouse cortex and analysed gene expression profiles of TBR2+ IPCs versus TBR2- cell populations. We identified different levels of key genetic factors regulating chromatid segregation, cell-cycle progression, transcription, and cell signaling. Remarkably, in humans, mutations of several identified IPC genes are linked to various cortical malformations, like microcephaly and macrocephaly, corpus callosum defects, and neurological deficits. For example, mutations in the cohesin acetyltransferase ESCO2, one of the newly identified IPC genes, cause severe malformations including microcephaly. We showed that deficiency of ESCO2 in the developing mouse cortex leads to severe loss of IPCs, resulting in cortical malformation. We thereby demonstrate the identification of a central genetic factor of IPC genesis. Our molecular profiling data reveal novel molecular characteristics of IPCs and offer a resource for future investigations. Recent sequencing analyses of cortical malformations revealed a multifarious genetic landscape. In our pilot work, we identified novel microcephaly-related mutations in a gene encoding EXOSC10, a core subunit of the RNA-decay exosome complex. In the second part of this work, we characterized the cortical phenotypes of EXOSC10cKO mutants. We showed that EXOSC10 is essential for forebrain formation. EXOSC10 deficiency in the developing mouse cortex causes massive apoptosis in cortical cells resulting in cortical malformation. We found that EXOSC10 binds and degrades mRNA coding for P53 signaling-mediators, like AEN and BBC3. Additionally, our studies indicate that EXOSC10 plays a role in regulating the differentiation of cortical progenitors. It might do so via degrading transcripts of the SHH/WNT-β catenin signaling pathways. Further investigations are needed to illuminate this additional role of EXOSC10. In conclusion, our study reveals an essential role of EXOSC10 in suppressing the P53, SHH/WNT-β catenin pathways, which are indispensable for cell survival, neurogenesis and normal cortical formation. Our findings of the mouse model correspond to observations of humans with microcephaly linked to EXOSC10 mutations.
Keywords: microcephaly; epigenetics; EXOSC10; ESCO2; development; neuroscience; cortex; neurodevelopment; malformation; RNA degradation; cortical development; IPCs; intermediate progenitors
 
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