Introduction

1 Forebrain asymmetry and the parapineal organ

Lead Author and Researcher
Dr V Chong-Morrison (Senior Postdoctoral Scientist)

Principal Investigators

Professor S Wilson (University College London)
Professor T Sauka-Spengler (University of Oxford/Stowers Institute)

This website is an active documentation of the bioinformatics underlying the following study.

1.1 Background

Left/right differences in the brain have fascinated thinkers for generations. Zebrafish genetic tools harnessed within the epithalamus of the forebrain has led to the habenula’s emergence as a powerful paradigm to understand brain lateralisation. During development in the embryo, the habenula forms bilaterally as a pair of left and right nuclei, along with a medial pineal gland, and left-sided parapineal nucleus that emerges from the pineal.

1.1.1 The parapineal organ

A substantial body of research in zebrafish unequivocally identified the parapineal organ (also known as the “parietal eye” in other organisms) as a crucial determinant of habenular left/right asymmetry. Through an unidentified mechanism, the parapineal organ signals to newly-born habenular neurons to adopt “left-sided” characteristics. This elusive signal is potent and precise within a defined developmental time window - approximately 28 to 32 hours post-fertilisation. Removing the parapineal signal during this time leads to a complete loss of left identity, resulting in a “double right” 4-days-old habenula.

The parapineal organ of a zebrafish embryo signals to neurons in the habenula region (dotted circles) circa 32 hours post fertilisation to acquire left/right asymmetric nuclei by 4 days old.

1.1.2 The sox1a gene

Previous studies have demonstrated that the parapineal organ expresses sox1a during its development. Lekk et al. showed that zebrafish sox1a mutants have “double right” habenula despite the parapineal developing normally in appearance. This finding was important as it uncoupled the parapineal’s signalling role from its anatomical structure. Unlike ablating or removing the parapineal altogether, which also leads to “double right” habenula, sox1a mutants can be utilised as a vehicle to retrieve signalling-deficient parapineal organs. These would uncover the important signal(s) crucial for habenula neurons to acquire left-sided character.

1.1.3 Current work

Identifying the parapineal signal(s) has previously eluded the field due to non-trivial technical challenges. At fewer than 20 cells per zebrafish embryo, isolating a pure population of parapineal cells of sufficient quality to characterise their genetic content was monumentally difficult. By combining single cell sequencing technologies with prior expertise in characterising small cell populations from zebrafish embryos, I overcame these challenges to illuminate a cohort of biological factors responsible for parapineal function in the context of epithalamic asymmetry.

1.2 Key references

  1. I. Lekk, V. Duboc, A. Faro, S. Nicolaou, P. Blader and S.W. Wilson. Sox1a mediates the ability of the parapineal to impart habenular left-right asymmetry. eLife (2019), e47376, 8, https://doi.org/10.7554/eLife.47376
  2. V. Duboc, P. Dufourcq, P. Blader, and M. Roussigné. Asymmetry of the Brain: Development and Implications. Annual Review of Genetics (2015), 647-672, 49(1), https://doi.org/10.1146/annurev-genet-112414-055322