I graduated from Cambridge University with a BA in Natural Sciences (Zoology) in 1990, then went to Dundee University to carry out PhD research on the regulation of cell division in fruit flies.  In 1995 I went to Stanford University in California for a period of post-doctoral research, concentrating on the role of specific genes co-ordination of various cellular events during sperm production in flies.  In 1998 I moved to Oxford to set up my own lab, initially as a departmental lecturer, and in 2001 earned Royal Society University Research Fellowship.  I continued to focus on spermatogenesis in Drosophila, specifically looking at regulation and function of testis specific genes.  In April 2008 I moved to Cardiff University, to take up a position as a Senior Lecturer, continuing with the fly testis research. I was promoted to Reader in 2011 and to Professor in 2014.

Regulation of Gene Expression in Drosophila Spermatogenesis

Cell differentiation is driven by co-ordinated changes in the gene expression profile of the cell: some genes are switched on, others are switched off.  One of the most astonishing developmentally regulated changes in cell morphology occurs in spermatogenesis.  The mature sperm is a highly specialised cell, whose formation from a simple primary spermatocyte involves an unusual cell division (meiosis) to form a round spermatid, followed by complex changes in the cell architecture to form the final elongated motile sperm.  These differentiation events require many gene products used at no other time in development.  Underlying this there is a dramatic switch in the gene expression profile of male germ-line cells: as they enter the primary spermatocyte stage they activate transcription of a large set of genes required for sperm production.  We have recently discovered that another small set of genes is transcribed after meiosis, in elongating spermatids, and are investigating their role in sperm function.

The meiotic arrest loci

The meiotic arrest class of Drosophila genes regulate transcription in spermatogenesis; specifically they are required for activation of expression of numerous genes required for spermatid differentiation.  A series of micro-array experiments revealed that approximately half of all Drosophila protein coding genes are expressed in testes, and that 15-20% of these are regulated by our genes, ie, the meiotic arrest genes control transcription of up to 10% of all Drosophila protein coding genes.  We cloned and characterised five of these meiotic arrest genes (aly, comr, achi/vis, topi and tomb). aly and comr have unknown functions, topi, tomb and achi/vis encode DNA binding proteins.  In normal primary spermatocytes all the meiotic arrest proteins are chromatin associated, consistent with their role in gene-expression regulation. Their localisation in different mutant backgrounds varies: e.g. aly function is required for the nuclear localisation of Comr, and vice versa, indicating that formation and localisation of an active complex is highly regulated.  We are currently investigating the formation of the complex, and its activity at target promoters.

Gene function in spermatogenesis

In 1998 I drew a model of the function of the meiotic arrest genes, in which I postulated that aly would regulate many genes required for spermatid differentiation.  This model was based on expression data for about 20 genes.  The array experiment was designed to test the model with many more genes.  However, the main observation revealed by the array analysis is that we know very little about gene function in Drosophila spermatogenesis.  I could initially not answer my question "do the meiotic arrest loci predominantly regulate genes required for spermiogenesis, and not genes required before meiosis?" because the function of the majority of genes that changed significantly in the mutants was not known.  We therefore began a large-scale functional-genetics project in which we are using RNA in situ hybridisation to describe the expression pattern, and genetic regulation, of more than 1000 genes in testes.  We have examined the expression patterns of about 1200 genes, and it seems my initial prediction was correct – genes that act after meiosis tend to be regulated by the meiotic arrest genes, whereas genes that act earlier tend not to require the meiotic arrest genes for their expression.

Post-meiotic gene expression in Drosophila

It has been generally accepted that there is no post-meiotic transcription in Drosophila spermatogenesis.  However, in our in situ hybridisation project, we have identified about 25 genes that are transcribed during the elongation stage of spermatid development.  Moreover, their transcripts are localised to the distal ends of the spermatids.  The localised transcripts fall into two classes - "cups" and "comets".  A mutation in one of the comet genes, scotti, is male sterile, with defects late in spermatogenesis.  We are using in vivo reporter constructs and genetic analysis to examine the mechanisms controlling the mRNA and protein localisations and functions.

Watch a video about why sperm are so interesting

Funding

Research in my lab is funded by BBSRC.

Group members

• Dr Katia Jindrich
• Mr Robert Mitchell

Postgraduate research students

• Mr Shrinivas Dighe
• Miss Fiona Messer
• Miss Cristina Fernadez Garcia

mRNA localisation to specific sub-cellular regions is a widespread phenomenon in polarised cells and is critical both during development (eg for patterning) and in differentiated cell types (eg for long term memory). Subcellularly localised mRNAs must interact with specific RNAbinding proteins to ensure their normal localisation/anchoring. Typically they are also under translational controls, to ensure they are only translated when at the target location. These phenomena have been studied in several systems, most notably in developmental patterning, cell migration and neurons. However many subcellularly localised mRNAs have been discovered through high-throughput studies, and the mechanisms underlying their localisation and translation have not been investigated.

We have discovered a set of localised mRNAs, which are found specifically at the growing ends of Drosophila spermatids, in patterns resembling comets or cups. We also discovered a set of known RNA-binding proteins that also localise to this region. In this project you will investigate potential roles of the RNA-binding proteins in localising these specific mRNAs. RNA localisation and translation will be investigated in RNA-binding protein mutants. Protein- RNA interactions will be assayed in vitro with both purified components and extracts (to allow ternary complex formation). You will also determine whether, and how, mutations in the localised mRNAs and RNA-binding proteins affect the intricate structure of developing spermatid tail tips.

This will provide the basis for a further analysis of this novel and virtually uncharacterised set of localised mRNAs. For example, systems biology and mathematical modelling approaches can be applied once the basic parameters of localisations, using super-resolution methods, and interactions at the biochemical and functional levels have been determined.

Objectives
-To describe and compare the comet and cup mRNAs’, and RNA-binding proteins’, localisations at the growing ends of spermatids.
-To determine whether the known RNA-binding proteins are important for localisation of any comet and cup mRNAs.
-To identify and characterise direct (or indirect) protein-RNA binding interactions between the localised mRNAs and the RNA-binding proteins.
-To investigate whether mutations in comet and cup genes, and the RNA-binding proteins, cause defects in the cellular structure at the growing ends of elongating spermatids.
-To uncover the relationship between "comet" and "cup" transcript localisation patterns.
-To determine whether the known RNA-binding proteins regulate comet and cup mRNA translation.

Eligibility

This studentship is available to UK and EU nationals who have established UK residency (EU nationals must have ordinarily lived in the UK throughout the three years preceding the start of the studentship). Please refer to the DTP eligibility webpage for more details: https://www.swbio.ac.uk/programme/eligibility/
Cardiff University will be able to award up to one fully funded four-year studentship for EU students who do not meet the residency requirements.

Entry requirements

Please refer to the DTP eligibility webpage for academic entry requirements: https://www.swbio.ac.uk/programme/eligibility/
If English is not your first language, you will need to achieve an IELTS score of 6.5 with 6.5 in all skills.

How to apply

Make your application to Cardiff University: https://www.cardiff.ac.uk/study/postgraduate/applying/how-to-apply
Please ensure that your application includes:
Two references. Neither of the referees should be part of the supervisory team.
Academic transcripts / degree certificate(s)
Personal statement. Please include supporting evidence for your Maths background.
Curriculum Vitae (CV)
English language certificates (where applicable)
Please refer to the DTP webpage for information about the selection process: https://www.swbio.ac.uk/programme/selection-process/

Applications must be submitted by midnight on Monday 2nd December 2019.

Funding Notes

This studentship will provide a stipend for 4 years in line with UK Research and Innovation (Research Council) rates (£15,009 in 2019/20), payment of university tuition fees, and a Research and Training and Support Grant (RTSG) to support the project.