RESEARCH

Zebrafish Sensory Lateral Line  

Our research program aims to dissect complex developmental and regenerative processes in vivo and at high resolution. We are studying these processes both at the cellular and molecular/genomics level.

We have identified the sensory lateral line of the zebrafish as a relatively simple system to shed light onto the molecular and cellular basis of complex vertebrate development and regeneration. The lateral line is an ideal organ to mechanistically dissect embryonic and post-embryonic processes because of 1) the accessibility of the sensory organs to direct observation and manipulation; 2) the relative simplicity of the lateral line system; 3) the similarity between lateral line hair cells and inner ear hair cells; 4) their ability to regenerate; and 5) the genetic tools available in zebrafish to molecularly dissect lateral line development (Lush et al. 2014 Dev Dyn; Kniss, Piotrowski 2016; Denans et al., 2019).

The lateral line is a sensory system for the detection of water movements to capture prey, avoid predators and schooling. The mechanosensory organs (neuromasts) are distributed in lines on the head and along the flanks of the animal. Neuromasts contain hair cells that are very similar to the hair cells in mammalian ears. Despite the unusual location of the hair cells in the skin, lateral line and ear hair cells develop by similar mechanisms and are derived from cephalic placodes. However, in contrast to the otic placode, the lateral line placode (also called primordium) undergoes a remarkable posterior migration towards the tail tip. This migration is a dynamic event that involves the primordium periodically depositing neuromasts until it reaches the tail tip, patterning the future lateral line.
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Hair Cell Regeneration (transcriptional control, epigenetics, innate immune system)

Humans in particular, and mammals in general, fail to regenerate mechanosensory hair cells in their inner ears leading to deafness. In contrast, fish, chicken and amphibians constantly replace dying hair cells through proliferation and differentiation of support cells. The molecular changes that prevent mammals from mounting a regenerative response are not understood. The major limitation is that the gene regulatory network underlying hair cell regeneration in lower vertebrates has not yet been elucidated. However, the knowledge of the precise timing when pathways are inhibited or activated during the regeneration process is important to design more sophisticated therapeutic strategies to induce mammalian hair cell regeneration. To determine the mechanisms that sustain a life-long ability to regenerate hair cells in fish we have been taking a multi-pronged approach:

• Determine the cell behaviors and cell lineages during regeneration
• Perform transcriptome analyses during homeostasis and regeneration (bulk and scRNASeq)
• Characterization of the epigenome during regeneration (ATAC and ChIPSeq)
• Characterization of the innate immune system involved in regeneration (scRNASeq, cell behavior)
• Mutagenesis screen to identify regeneration genes (ENU and CRISPR)

Cell migration and sensory organ development
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Cell migration is a tightly coordinated but not well understood process during development. Elucidating the underlying mechanisms is not only important for embryonic development but is also highly relevant for cancer biology. Our work has greatly contributed to establishing the migrating lateral line primordium as a model for collective cell migration. We have identified important cell-cell signaling events that occur between cells in the leading and trailing zones of the migrating lateral line primordium (Aman and Piotrowski, 2008). We demonstrated that the activation of Fgf signaling by Wnt/β-catenin in trailing cells crucially depends on heparan sulfate proteoglycans (Venero Galanternik etal., 2015). In turn, Fgf signaling activates Notch signaling which controls organ size via the regulation of cell adhesion (Kozlovskaja-Gumbriene et al.,2017). We also discovered that the primordium deposits a trail of interneuromast cells in between these neuromasts which represent stem cells that give rise to postembryonic neuromasts (Grant et al., Neuron 2005, Lush et al., eLife 2014). In addition, we have made the important finding that non-canonical wnt11 (wnt11f1) regulates orientation of the sensory hair cells independently of the PCP pathway (Navajas Acedo et al., 2019). In a recent study we describe our discovery of ionocytes that invade the sensory organs and ensure proper hair cell function (Peloggia, Muench et al., 2021). The complex cellular signaling interactions resulting in the integration of stem cell regulation, cell fate specification and migration and to what extent these mechanisms are conserved during hair cell regeneration remain a mystery and form a central focus for our research.