Embryonic and post-embryonic organogenesis in the medaka lateral line

Organs are functional units of multicellular organisms. Although the body can compensate for minor deficiencies in organ function in some cases, generally, survival of the organism depends on organ integrity . A critical step in the life of multicellular organisms is therefore organogenesis, which needs to be tightly regulated to prevent pathologic conditions. This thesis deals with the formation of stereotypic patterns on the organ and organ system level during embryonic and post-embryonic development of the Japanese rice fish medaka (Oryzias latipes). The lateral line has been widely used as a model to study a variety of developmental processes. The lateral line is a sensory organ system of fish and aquatic amphibia that is used to detect water movement. It consists of small organs, so-called neuromasts, that are distributed bilaterally in stereotypic patterns across the entire surface of the animal. All embryonically formed neuromasts originate from specialized regions of head ectoderm (placodes) and from there populate the entire body via migrating primordia or sensory ridges. The lateral line can be divided into the anterior lateral line (aLL), including all neuromasts on the head, and the posterior lateral line (pLL), consisting of neuromasts on the tail. While the embryonic development of pLL neuromasts via a migrating primordium has been extensively studied, the embryonic development of aLL neuromasts remains vastly understudied. This is potentially due to the complexity of the aLL system. I quantified position and number of aLL neuromasts of medaka in detail based on a previously published atlas, which defines nine distinct aLL sub-lines, according to innervation. Quantification of neuromast numbers revealed that some aLL sub-lines are characterized by variability in organ number, similar to the pLL, while other aLL sub-lines are highly stereotypic and display perfect symmetry among the left and right side of the same fish. In addition, I started to uncover the developmental mechanisms building the aLL in medaka. Using live-imaging, whole-mount immunohistochemistry and in situ hybridization, I was able to identify sensory ridges as the tissue of origin for the majority of aLL neuromasts. The remaining few neuromasts are generated by a migrating primordium that relies on chemokine signaling via Cxcr4b, similar to the pLL primordium. Furthermore, results from genetic and non-genetic perturbation experiments during embryonic development indicate that interactions with the surrounding tissue are an integral part of aLL development. Moreover, differential responses to perturbation in different aLL sub-lines suggest diverse developmental mechanisms within the aLL. Like amphibians and some reptiles, fish display the remarkable feature of indeterminate growth. Neuromasts adjust to an ever-growing body by increasing in size, but also by generating additional organs post-embryonically from pre-existing neuromasts all over the body. The caudal neuromast cluster (CNC) is a group of neuromasts located on the caudal fin. Previous experiments from our lab have shown that in medaka all neuromasts in the CNC are derived from a single organ that was deposited on the caudal fin during embryonic development. The CNC is exceptionally well suited to study post-embryonic organogenesis due to its stereotypic location, accessibility for imaging and early onset of post-embryonic organogenesis. Using a combination of live-imaging, genetic tools and immunohistochemistry, I was able to start deciphering the mechanism of post-embryonic organogenesis on the tissue level. Briefly, a subset of neuromast stem cells that we termed organ-founder stem cells, undergoes an epithelial- to-mesenchymal transition (EMT), migrates out of a founder neuromast and generates a post- embryonic organ in a highly stereotypic manner. The results acquired in this thesis indicate that stem cell migration is influenced by interactions with the surrounding tissue, specifically at the anterior side of the founder neuromast. Although the full mechanistic understanding of these tissue interactions remains elusive, my findings suggest that chemokine signaling via Cxcr4b and interaction with the vasculature are involved in the regulation of stem cell migration. I discuss these results in light of diseases in mammals. Possibly, molecular routes that are used under physiological conditions in fish, can be hijacked by cells in mammals, leading to pathologies.