ERC FUNDED PROJECTS

Centrosomes are the main microtubule-organizing centers of animal cells. They influence the morphology of the microtubule cytoskeleton and function as the base of primary cilium, a nexus for important signaling pathways. Structural and functional defects in centrosome/cilium complex cause a variety of human diseases including cancer, ciliopathies and microcephaly. To understand the relationship between human diseases and centrosome/cilium abnormalities, it is essential to elucidate the biogenesis of centrosome/cilium complex and the control mechanisms that regulate their structure and function. To tackle these fundamental problems, we will dissect the function and regulation of centriolar satellites, the array of granules that localize around the centrosome/cilium complex in mammalian cells. Only recently interest in the satellites has grown because mutations affecting satellite components were shown to cause ciliopathies, microcephaly and schizophrenia. Remarkably, many centrosome/cilium proteins localize to these structures and we lack understanding of when, why and how these proteins localize to satellites. The central hypothesis of this grant is that satellites ensure proper centrosome/cilium complex structure and function by acting as transit paths for modification, assembly, storage, stability and trafficking of centrosome/cilium proteins. In Aim 1, we will identify the nature of regulatory and molecular relationship between satellites and the centrosome/cilium complex. In Aim 2, we will elucidate the role of satellites in proteostasis of centrosome/cilium proteins. In Aim 3, we will investigate the functional significance of satellite-localization of centrosome/cilium proteins during processes that go awry in human disease. Using a multidisciplinary approach, the proposed research will expand our knowledge of the spatiotemporal regulation of the centrosome/cilium complex and provide new insights into pathogenesis of ciliopathies and primary microcephaly.

1 499 819 €

Start date: 2016-06-01, End date: 2021-05-31

Oriented cell divisions dictate morphogenesis by shaping tissues and organs of multicellular organisms. Oriented cell divisions have profound influence in plants because their cell positions are locked by shared cell walls. A relay of cell divisions involving precise division plane switches determines embryonic body plan, organ layout and organ architecture in plants. Cell division planes in plants are specified by reorganization of premitotic cortical microtubule array and how this occurs is a long-standing key question. My recent results establish, for the first time in plants, an in vivo inducible and traceable, precise 90º cell division plane switch system. With this system I identified a pathway that proceeds from transcriptional activation through a signaling module all the way to the activation of microtubule regulators that orchestrate switches in premitotic microtubule organization and cell division planes. My findings provide a first paradigm in plants of how genetic circuitry patterns cell division planes via feeding onto cellular machinery and pave the way for unraveling mechanistic control of cell division plane switch. By establishing a precise cell division plane switch system I am in a unique position to answer: 1. What transcriptional program and molecular players control premitotic microtubule reorganization? 2. Which mechanisms switch premitotic microtubule array? 3. What influence do identified players and mechanisms have on different types of oriented cell divisions in plants? For this I propose a systematic research plan combining (i) forward genetics and expression profile screens for identifying a suite of microtubule regulators, (ii) state-of-the-art microscopy and modeling approaches for uncovering mechanisms of their actions and (iii) their tissue-specific manipulations to modify plant form. By unraveling players and mechanisms this proposal shall resolve regulation of oriented cell divisions and expand plant engineering toolbox.

1 500 000 €

Start date: 2013-01-01, End date: 2017-12-31

Daylength measuring devices such as the photoperiodic timer enable animals to anticipate and thus survive adverse seasons. This ability has contributed to the great success of insects living in temperate regions. Yet the basis of photoperiodic sensing remains elusive, because of the lack of suitable genetic models expressing photoperiod-dependent seasonal phenotypes. We have developed the linden bug, Pyrrhocoris apterus, into a genetically tractable model with a robust, photoperiod-dependent reproductive arrest (diapause). With the available tools, this insect has become ideal for deciphering the regulation of seasonality. The project has 3 clear and ambitious objectives: 1). Our goal is to define the molecular and anatomical bases of the photoperiodic timer. To achieve this, we propose to identify photoperiodic timer genes, genes regulating input to the timer, and early output markers, through an RNA interference screen(s). To define the molecular mechanism of the timer, we will employ genome editing to precisely alter properties of the key players. 2). Next, we will combine techniques of neuronal backfilling, in-vivo fluorescent reporters, and microsurgery to define the photoperiodic timer anatomically and to examine its spatial relationship to the circadian clock in the insect brain. 3). We will exploit the great natural geographic variability of photoperiodic timing in P. apterus to explore its genetic basis. Genetic variants correlating with phenotypic differences will be causally tested by genome editing within the original genetic backgrounds. Both the established and the innovative strategies provide a complementary approach to the first molecular characterization of the seasonal photoperiodic timer in insects. The proposed research aspires to explain mechanisms underlying the critical physiological adaptation to changing seasons. Deciphering mechanisms underpinning widespread adaptation might bring general implications for environment-friendly pest control.

2 000 000 €

Start date: 2017-04-01, End date: 2022-03-31

Programmed cell death (PCD) is a fundamental biological process that actively terminates a cell’s vital functions by a well-ordered sequence of events. In both animals and plants, various types of PCD are crucial for development, health, and the responses to various stresses. Despite their importance, only little is known about PCD processes and their molecular control in plants. Still, an intricate regulatory network must exist that renders specific plant cell types competent to initiate and execute PCD at precisely determined developmental stages. I recently established a powerful developmental PCD model system in Arabidopsis thaliana, based on a PCD process occurring during root cap development. This root cap model has the potential to revolutionize existing concepts of plant PCD, as it combines a precisely predictable PCD process in easily accessible cells on the root periphery with the abundance of resources available for Arabidopsis research. Exploiting the root cap system will enable me to tackle unresolved fundamental questions about the regulation of developmental PCD in plants: How do cells acquire PCD competency during differentiation? Which signals trigger PCD execution at just the right moment? What are the actual mechanisms that disrupt the vital functions of a plant cell? I will obtain answers to these questions through a comprehensive strategy combining complementary approaches, taking advantage of cell-type specific transcriptomics, forward and reverse genetics, advanced live-cell imaging, biochemistry, and computational modeling. Our unpublished data point to the existence of a common core mechanism controlling PCD not only in the root cap, but also in other vital organs including the vasculature, anthers, or developing seeds. Thus, this project will not only be significant to advance our knowledge on PCD as a general developmental mechanism in plants, but also to generate new leads to tap the so far underexploited potential of PCD in agriculture.

1 499 746 €

Start date: 2015-04-01, End date: 2020-03-31