Temporal Coordination of Stem Cell and ECM Dynamics in L1 Animals

The external skeleton of nematodes, also called the cuticle, is a complex, multi-layered extracellular matrix secreted by underlying epidermal cells. The cuticle maintains the shape of the worm, provides a frame for the attachment of muscles, protects the organism from desiccation or injury, and participates in the uptake of nutrients. The various layers of the cuticle perform distinct functions and, accordingly, consist of different molecular assemblies. The precise biochemical composition and ultrastructure of the cuticle changes with every molt, presumably to accommodate the needs of the developing organism.

At every molt, the epidermis detaches from the old cuticle (apolysis) and secretes a new one; outermost layers first. Particular components of the old cuticle are likely degraded and possibly recycled. Attachment complexes between the cuticle, the epidermis, and the underlying basement membrane associated with body wall muscles are also remade or remodeled. When the new cuticle is functional, the animal can safely escape the old skeleton (ecdyse).

The major goal of our laboratory is to define the signaling pathways and enzymatic cascades that promote remodeling of the epidermis and related extracellular matrices during molting. Because collagens are the predominant structural components of the cuticle, similar to human skin and connective tissue, findings related to the nematode molting cycle may apply to the matrix biology of vertebrates.

We are currently investigating the functions of particular genes essential for release of the old cuticle and exploring potential regulatory relationships among the corresponding proteins. We are most interested in conserved extracellular proteins including the low-density lipoprotein receptor-like protein LRP-1, particular proteases and anti-proteases, and the fibrillin-like FBN-1. We expect our ongoing studies of molting to uncover conserved molecular pathways important for normal development and wound healing in mammals. Dysfunction of these processes in humans is a hallmark of metastatic cancer, fibrosis, and various inherited disorders of skin and connective tissues such as Marfan Syndrome.