The big picture
The Rasmussen lab uses zebrafish to gain molecular and cellular insights into neuronal and tissue plasticity, both during development and following injury. The skin is our largest sensory organ and is densely innervated by somatosensory nerve endings that sense pain and touch. Nerve regeneration is often incomplete following skin injury, and sensory loss is a major complication associated with diabetes and chemotherapy. Using the imaging advantages of the zebrafish system and novel remodeling assays developed in the lab, we have identified interactions between somatosensory nerve endings and several specialized cell types (including osteoblasts, resident macrophages, and mechanosensory cells) within the skin tissue environment. We are currently pursuing the following related projects:
- Control of nerve patterning during skin development
- Genomic and cellular analysis of nerve regrowth following injury
- Development, regeneration, and function of mechanosensory cells
Whereas many of the key events in skin and somatosensory development occur in utero in mammals – making them relatively inaccessible – the external development of zebrafish allows for facile observation and manipulation of maturing skin. The Rasmussen lab uses the genetic and imaging advantages of zebrafish to study nerve remodeling in a living vertebrate with single-cell resolution. Since zebrafish can regenerate almost any adult structure (Rasmussen and Sagasti, 2017), they are an excellent system for identifying mechanisms of successful nerve and tissue repair.
Project 1: Control of nerve patterning during skin development
As animals mature from embryonic to adult stages, the skin grows and adds epithelial strata, specialized cells, and dermal appendages (e.g., hairs, feathers, and scales) (see figure). How somatosensory nerves adapt to these dramatic changes in their target tissue is poorly understood. By examining juvenile fish, the lab previously discovered that skin innervation dramatically remodels following scale development. In contrast to the simplified larval innervation pattern, which is driven by growth and repulsion of naked axon endings, adult axons enter the epidermis as evenly spaced nerves, suggesting an alternative mechanism for spacing axon endings in adult skin. Surprisingly, a subset of dermal osteoblasts involved in scale formation independently guide nerves and vasculature during development and regeneration (Rasmussen et al., 2018). We are currently investigating the mechanisms that regulate osteoblast patterning of nerves and vasculature.
Project 2: Genomic and cellular analysis of nerve regrowth following injury
The skin is our primary barrier to the external environment and faces constant environmental insults (e.g., injury, ultraviolet light), and the somatosensory nerves that innervate the skin are frequently damaged. Nerve injury triggers an axon destruction program known as Wallerian degeneration, which creates large amounts of axon debris in the skin. Removal of cellular debris is essential for tissue repair, but the mechanisms used to repair somatosensory nerves are not well understood. By using live imaging and laser axotomy in larval zebrafish, we made the unexpected finding that keratinocytes, not macrophages, eat axon debris following skin injury (see figure). Keratinocytes eat several additional types of cellular debris (Rasmussen et al., 2015), suggesting that keratinocyte phagocytosis may play a broad, yet underappreciated, role in tissue repair. We are extending these studies to understand the cellular and transcriptional mechanisms that regulate axon debris clearance and regrowth in the more complex adult skin.
Project 3: Development, regeneration, and function of mechanosensory cells
Somatosensory nerves innervate a diverse set of specialized sensory structures in the skin. Merkel cells are keratinocyte-derived mechanosensory cells that were first described over 100 years ago. Recent work in rodents has shown that Merkel cells form synapse-like connections with somatosensory endings and detect touch. We have identified markers of Merkel cells in zebrafish (see figure), and we are developing genetic and functional assays to probe unanswered questions in Merkel cell development and regeneration.