Biology subjects

Heinen, J. P.

Publications and source records attributed to Heinen, J. P..

3 recordsLinked to original sources

bioRxiv2023

The Drosophila cancer-germline, head-to-head gene pair TrxT and dhd is dispensable for normal brain development but plays a major role in l(3)malignant brain tumour growth.

Drosophila thioredoxins Deadhead (Dhd) and Thioredoxin-T (TrxT) are encoded by a head-to-head gene pair in the X chromosome. Akin to human cancer-germline (CG) genes, dhd and TrxT expression is normally sex and germline specific, but becomes upregulated in brain tumours of either sex caused by mutation in l(3)malignant brain tumour (l(3)mbt). Using CRISPR/Cas9-mediated knock-out alleles and RNA-seq, we show that while both TrxT and dhd are dispensable for normal brain development, each of them has a significant but partial effect on l(3)mbt brain tumour development as well as on tumour-linked transcriptomic signatures. Moreover, this effect is enhanced by the concomitant removal of both thioredoxins that strongly inhibits l(3)mbt larval brain tumour traits, reduces gene expression differences between tumour and wild-type tissue, and essentially erases all traces of gene expression differences between tumours from larvae of different sex. These results show that TrxT and dhd play a major synergistic role in the emergence of l(3)mbt tumour-linked transcriptomic signatures and tumour development, which is remarkable taking into account that these two genes are never expressed together under normal conditions. We have also found that TrxT is crucial but dhd has no effect on the growth of male-derived l(3)mbt allografts, hence suggesting that the initial stages of tumour development and sustained, long-term tumour growth may depend upon different molecular pathways. In humans, head-to-head inverted gene pairs are abundant among the CG genes that map to the X chromosome, some of which have been shown to work as a unit cancer. Our results identify the first instance of an X-linked, head-to-head CG gene pair in Drosophila and underpin the potential of such CG genes that are dispensable for normal development and homeostasis of somatic tissue, as targets to curtail malignant growth with minimal impact on overall health.

cancer biology↗

bioRxiv2021

Tumour Suppressor Parafibromin/Hyrax Governs Cell Polarity and Centrosome Assembly in Neural Stem Cells

Neural stem cells (NSCs) divide asymmetrically to balance their self-renewal and differentiation, an imbalance in which can lead to NSC overgrowth and tumour formation. The functions of Parafibromin, a conserved tumour suppressor, in the nervous system are not established. Here, we demonstrate that Drosophila Parafibromin/Hyrax (Hyx) inhibits NSC overgrowth by governing cell polarity. Hyx is essential for the apicobasal polarization of NSCs, through its role in the asymmetric distribution of polarity proteins. hyx depletion results in the symmetric division of NSCs, leading to the formation of supernumerary NSCs in the larval brain. Importantly, we show that human Parafibromin can fully rescue NSC overgrowth and cell polarity defects in Drosophila hyx mutant brains. We have also discovered a novel role for Hyx in regulating the formation of interphase microtubule-organizing center and mitotic spindles in NSCs. Moreover, Hyx is required for the proper localization of a key centrosomal protein, Polo, and the microtubule-binding proteins Msps and D-TACC in dividing NSCs. Furthermore, Hyx directly regulates the polo expression in vitro. Altogether, our study provides the first evidence that the brain tumour suppressor-like role and polarity establishing functions of Hyx are mediated by its role in regulating microtubule growth and centrosomal assembly. The new paradigm that Parafibromin orchestrates cell polarization by regulating centrosomal assembly may be relevant to future studies on Parafibromin/HRPT2-associated cancers.

developmental biology↗

bioRxiv2021

Illuminati, a novel form of gene expression plasticity in Drosophila neural stem cells

With the aim of developing a genetic instability (GI) sensor in vivo we used the well-established Gal80/Gal4-UAS system combined with a visual GFP marker in Drosophila. We generated a collection of 25 Drosophila lines carrying GAL80 transgenes in different locations in all major chromosomes (X, Y, II, and III). We found low rates of GFP cells in epithelial tissues such as wing discs. In contrast, in larval brains, GFP positive clusters containing neural stem cells- also called neuroblasts (NBs)- and their offspring, were highly frequent. Using genetic and imaging-based approaches, we show that GFP NBs do not result from aneuploidy or mutations in the GAL80 gene, but rather by stochastic repression of GAL80 expression. We named this novel type of gene expression instability Illuminati. Importantly, Illuminati frequency is influenced by environmental and stress conditions. Further, we found that once established, Illuminati can be propagated over many cell cycles.

developmental biology↗