Throughout the lifetime of living systems, tissue homeostasis and renewal constantly take place to confront challenging conditions, both internally, such as cell aging, and externally, such as infections, so that health can be maintained. Such processes require a tight balance between cell proliferation and differentiation. When homeostasis is disturbed, diseases like cancer can develop. Therefore, understanding the regulation of tissue homeostasis is a key question in biology. However, directly monitoring the dynamics of proliferation and differentiation in live animals remains extremely challenging. Common methods, such as immunostaining and single-cell RNA sequencing, require killing the animal and fixing the cells. Therefore, they can merely provide information in a single time frame. As a result, lineage tracing techniques are introduced, where cells are labeled with a heritable marker that can be detected in progeny after a certain period by fluorescence microscopy or sequencing. Nevertheless, they only produce lineage dynamics indirectly.

Multicellular development is a sequence of genetically programmed, intricately linked micro- and macroscopic events that start from a single cell - zygote - and lead to the formation of a functional individual, primed for survival and reproduction. All developmental events, fromgene expression to cell division, differentiation andmigration, as well as tissue and organ formation, have to follow a precise temporal and spatial order, as the smallest mistake can be detrimental. Development is remarkably reproducible, despite occurring under a wide variety of environmental conditions, such as nutrient availability and temperature, and being subject to a substantial amount of molecular noise. In this thesis, we use the nematode worm Caenorabditis elegans as a model system to investigate i) how the timing of development adjusts to changes in the outside world and ii) how organisms respond to external stresses that do not support normal developmental progression. C. elegans is an ideal model organism to address these questions, due to its simplicity, stereotypical developmental pattern and the vast extent to which its biology and genetics are known.

Throughout their lifetime, animals face a wide variety of biological challenges. Starting out as single cells, their _rst challenge is to undergo development and become fully grown and functional adults. Remarkably, this incredibly complex process occurs in a highly reproducible manner despite the huge variability in environmental, genetic and molecular uctuations they encounter during their journey through development. However, the challenges do not end here; once animals become adults, their tissues are constantly subject to damage, either by external sources such as disease, or due to intrinsic causes such as cellular aging. Thus, adult tissues are constantly renewing themselves, and must do so in a tightly controlled manner in order to maintain homeostasis. In this thesis, we explore how animals cope with a few of such challenges with the help of two model systems, C. elegans worms and stem cell-derived organoids.