The big picture
How organisms establish and maintain complex cellular architectures is a fundamental problem in biology. Our skin is a sensory organ innervated by a fascinating array of intricately patterned somatosensory axon endings. Loss of sensory function in the skin is debilitating and associated with common genetic and acquired disorders, such as Charcot-Marie-Tooth disease and diabetic peripheral neuropathy. Thus, understanding the fundamental cellular and molecular mechanisms involved in somatosensory axon development and repair will have important disease implications.
Why zebrafish skin?
Whereas many of the key events in skin organogenesis 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 has developed the zebrafish skin as a powerful genetic system 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 tissue repair.
Project 1: How is vertebrate skin innervation patterned?
As animals mature from embryonic to adult stages, the skin grows and adds epithelial strata, specialized cells and dermal appendages, like hair, glands and scales (see figure). How cutaneous axons adapt to these dramatic changes is poorly understood. By examining juvenile fish, the lab previously discovered that skin innervation dramatically remodels following appendage 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. Adult sensory nerves contain Schwann cells, blood vessels and osteoblasts, and a subset of dermal osteoblasts independently guide nerves and blood vessels during development and regeneration. By preventing scale regeneration and examining mutants lacking scales, we showed that scales coordinate axon remodeling and skin maturation (Rasmussen et al., 2018). Since many animals have regularly spaced dermal appendages related to scales, these results raise the intriguing possibility that skin appendages may provide a general mechanism for patterning innervation during organogenesis.
Project 2: How do skin phagocytes contribute to tissue repair?
The skin is our largest sensory organ, and axons that innervate the skin are frequently damaged. Removal of cellular debris is essential for tissue repair, but the mechanisms used to repair sensory endings 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 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 currently extending these studies to understand the cellular and molecular mechanisms that regulate axon removal in the more complex adult skin.