Biology subjects

Guilgur, L. G.

Publications and source records attributed to Guilgur, L. G..

3 recordsLinked to original sources

bioRxiv2018

Delayed aneuploidy stress response of neural stem cells impairs adult lifespan in flies

SummaryStudying aneuploidy during organism development has strong limitations, as chronic mitotic perturbations used to generate aneuploidy result in lethality. We developed a genetic tool to induce aneuploidy in an acute and time controlled manner during Drosophila development. This is achieved by reversible depletion of cohesin, a key molecule controlling mitotic fidelity.\n\nLarvae challenged with aneuploidy hatch into adults with severe motor defects shortening their lifespan. Neural stem cells, despite being aneuploid, display a delayed stress response and continue proliferating, resulting in the rapid appearance of chromosomal instability, complex array of karyotypes and cellular abnormalities. Notably, when other brain cell-lineages are forced to self-renew, aneuploidy-associated stress response is significantly delayed, indicating that stemness state confers resistance to aneuploidy. Sparing solely the developing brain from induced aneuploidy is sufficient to rescue motor defects and adult lifespan, suggesting that neural tissue is the most ill-equipped to deal with developmental aneuploidy.\n\nHighlightsO_LIReversible depletion of cohesin results in just a round or two of aberrant cell divisions, generating high levels of aneuploidy.\nC_LIO_LILarvae challenged with aneuploidy during development hatch into impaired adults.\nC_LIO_LIFew cell cycles are sufficient for chromosomal instability to emerge from a previously stable aneuploid state.\nC_LIO_LINeural stemness delays aneuploidy stress response.\nC_LIO_LIProtecting only the neural tissue from aneuploidy rescues adult abnormalities and lifespan.\nC_LI

developmental biology↗

bioRxiv2018

Absence of the Spindle Assembly Checkpoint restores mitotic fidelity upon loss of sister chromatid cohesion

Sister chromatid cohesion is essential for faithful mitosis, as premature cohesion loss leads to random chromosome segregation and aneuploidy, resulting in abnormal development. To identify specific conditions capable of restoring defects associated with cohesion loss, we screened for genes whose depletion modulates Drosophila wing development when sister chromatid cohesion is impaired. Cohesion deficiency was induced by knock-down of the acetyltransferase Separation anxiety (San)/Naa50, a cohesin complex stabilizer. Several genes whose function impacts wing development upon cohesion loss were identified. Surprisingly, knockdown of key Spindle Assembly Checkpoint (SAC) proteins, Mad2 and Mps1, suppressed developmental defects associated with San depletion. SAC impairment upon cohesin removal, triggered by San depletion or artificial removal of the cohesin complex, prevented extensive genome shuffling, reduced segregation defects and restored cell survival. This counterintuitive phenotypic suppression was caused by an intrinsic bias for efficient chromosome bi-orientation at mitotic entry, coupled with slow engagement of error-correction reactions. We conclude that mitotic timing determines the severity of defects associated with cohesion deficiency. Therefore, although divisions are still error-prone, SAC inactivation enhances cell survival and tissue homeostasis upon cohesion loss.

cell biology↗

bioRxiv2018

The Trithorax group protein dMLL3/4 instructs the assembly of the zygotic genome at fertilization

The transition from fertilized oocyte to totipotent embryo relies on maternally-provided factors that are synthetized and accumulated in developing oocytes. Yet, it is still unclear how oocytes regulate the expression of these embryo fate-promoting genes within the general transcriptional program of oogenesis. Here we report that the Drosophila Trithorax group protein MLL3/4 (dMLL3/4, also known as Trr) is essential for the transition to embryo fate at fertilization. In the absence of dMLL3/4, oocytes develop normally but fail to initiate the embryo mitotic divisions after fertilization. This incapability results from defects in both paternal genome reprogramming and maternal meiotic completion. We show that, during oogenesis, dMLL3/4 promotes the expression of a functionally coherent gene subset that is later required for the correct assembly of the zygotic genome. Accordingly, we identify the evolutionarily-conserved IDGF4 glycoprotein (known as oviductin in mammals) as a new oocyte-to-embryo transition gene under dMLL3/4 transcriptional control. Based on these observations, we propose that dMLL3/4 plays an instructive role in the oocyte-to-embryo transition that is functionally uncoupled from the requirements of normal oocyte differentiation.

developmental biology↗