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UBC Theses and Dissertations

Spatiotemporal characterisation of some trascriptional signatures in early cerebellar development Gupta, Ishita


The cerebellum is an important part of the central nervous system (CNS). During early embryonic development, the neuroepithelium of the cerebellar primordium consists of two primary progenitor zones – the rhombic lip (RL) and the ventricular zone (VZ). All glutamatergic cells like granule cells arise from the RL while the GABAergic cells like Purkinje cells arise from the VZ. Each of the progenitor zones gives rise to multiple cell types in a distinct spatiotemporal sequence, but it is not clear what are the underlying genetics that control this sequence. Compartmentation of these progenitor zones has been an emerging field in this line of investigation. Using fluorescent RNA in situ hybridisation, I have characterised the Msx genes, a family of transcription factors downstream of BMP signaling, to show how they spatiotemporally pattern the cerebellar neuroepithelium. Msx1 is compartmentalised within the RL to likely maintain a progenitor pool, while Msx3 is compartmentalised within the VZ to likely be involved in the VZ progenitor fate specification. As external signaling molecules, the BMPs have been implicated in the specification of cerebellar cell types but their downstream molecular cascades are unknown. The results of this study present the Msx genes as strong candidates facilitating this BMP signaling in cerebellum development. In the second part of the study, I have utilised a time-course transcriptome to identify a catalog of brain specific long non-coding RNAs (lncRNAs) expressed significantly in the developing cerebellum. This class of non-coding RNAs is largely heterogenous and uncharacterised in their function. Recent studies, however, have implicated lncRNAs in the genetic regulation of CNS development. The top candidate lncRNA of the catalog, 6330403K07Rik, has been analysed for its spatiotemporal expression in the developing cerebellum. 6330403K07Rik has strong expression in the RL and nuclear transitory zone at E11.5 and in the glutamatergic cerebellar nuclear neurons at E18.5. This two-part study is aimed to further the genetic resolution of cerebellar development through gene expression studies. Developmental defects in the cerebellum are implicated in neurodevelopmental disorders such as Autism Spectrum Disorder, Schizophrenia and ADHD, and understanding the genetics of cerebellar development is important to developing therapeutic interventions.

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