Felton, Terry James; (2019) Cellular and molecular regulation of left-right asymmetric neurogenesis in the C. elegans C-lineage. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

To date, little is known about positive regulators of proneural gene expression. Using C. elegans as a model, we aim to address the cellular and molecular mechanisms required for the regulation of proneural gene expression during C-lineage neurogenesis. The C. elegans C-lineage is largely L/R bilaterally symmetric, however the anterior (left) lineage branch undergoes an asymmetric neurogenesis event, giving birth to two glutamatergic interneurons, DVC and PVR. We have previously shown that the proneural gene hlh-14/achaete-scute is expressed asymmetrically in the C-lineage and is required for this asymmetric neurogenesis event (Poole et al., 2011). In an effort to identify mechanisms that regulate hlh-14 expression, we have performed two screens: a GFP-based forward genetic screen and a 4D-lineage-based screen. To date, we have generated a collection of six asymmetric neurogenesis defective (and) mutants. In this thesis, I will show through mapping, complementation testing, and rescue experiments that one of the isolated mutants, and-4(t3273) is an allele of let-19/mdt-13, part of the Mediator complex, a conserved transcriptional regulator of asymmetric cell fate decisions (Yoda et al., 2005). I will also show that and-6(drp6) is an allele of hlh-2/daughterless, a bHLH transcription factor that heterodimerises with many other bHLH transcription factors, including hlh-14, to activate transcription (Grove et al., 2009). We find that in let-19 mutants hlh-14 expression is lost, the mother of DVC divides early, and DVC acquires a hypodermal fate. In hlh-2 mutants, a similar set of phenotypes is observed. Temporally, we find that let-19, likely acts just before the birth of Caap. Intriguingly, Caap is born from an unequal division regulated by let-19 and aligns with our observations of hlh-2 expression and its maintenance until the birth of DVC and PVR. Also interestingly, hlh-2 expression is abolished in let-19 mutants. Together our data suggest a novel role for the Mediator complex as a regulator of proneural gene expression. In this work, I will show that let-19 likely executes its role by regulating hlh-2, which in turn regulates hlh-14 asymmetric expression. Interestingly, let-19 regulation is independent of asymmetric localisation of POP-1, a known downstream regulator of asymmetric fate divisions. This suggests that let-19 acts either downstream or in parallel to POP-1.

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