A critical role for planar cell polarity (PCP)

During development, cells must be able to sense direction along a body or tissue axis to coordinate the collective cell movements that shape the embryo. Disruptions in the signaling pathways that provide directional information can lead to severe developmental defects, including shortened body axes, neural tube closure defects, and congenital heart defects. The highly conserved Planar Cell Polarity (PCP) pathway provides directional information by acting as a cellular compass, allowing cells to orient themselves and their behaviors along a common axis.  

Our lab is interested in two fundamental questions:

1. How is PCP organized?

2. How does PCP direct collective cell behaviors?

The core transmembrane PCP proteins have a remarkable ability to self-organize. Within a cell, Fzd6 and Vangl2 polarize towards opposite sides of the cell where they interact with the atypical cadherin Celsr1. Positive and negative feedback promotes the of clustering of like complexes and their segregation to opposite sides of the cell. Extracellularly, Fzd6-Celsr1 interacts with Vangl2-Celsr1 to directly link the axis of asymmetry between neighboring cells. Through the extracellular interactions, directional information is propagated across a tissue.

If self-organization were the only mechanism setting the axis of PCP polarity, we would expect tissues to polarize in any direction. However, PCP is consistently aligned along the same tissue axis in every animal. This has led to the hypothesis that directional cues define the tissue-level axis of polarity and bias PCP proteins to self-organize along the same axis. Our lab seeks to uncover the mechanisms that organize PCP from individual cell junctions to entire tissues.

Hair follicle orientation as a readout of PCP activity

Hair follicle orientation provides a striking readout of PCP across the entire skin. In the mouse, the PCP axis directs coordinated cell movements within the developing follicle, orienting it along the anterior-posterior axis. Because PCP is essential for embryonic development, its complete loss must be studied in epidermis-specific knockouts, which display whorls of hair across the entire body. Interestingly, distinct region-specific defects appear when PCP activity is only partially disrupted. Thus, the skin does not appear to be uniformly patterned, and the spectrum of hair phenotypes may reveal factors that alter either PCP self-organization or the directional cues that orient PCP across distinct regions.

Forward genetics with natural variants

Natural variants maintained by animal breeders offer a unique window into how PCP is organized across the skin. The rosette fancy mouse, which first appeared in a fancier's colony in the 1960s, has two large whorls restricted to the posterior half of its body. Unlike previously characterized PCP mutants, the Celsr1 remains strongly polarized and locally coordinated in rosette skin, but the axis of asymmetry rotates in the posterior region, where the PCP-directed cell movements that orient the follicle are reversed. This suggests that the PCP axis is flipped 180° in the posterior, consistent with an altered directional cue. 

The Abyssinian guinea pig, a breed documented as early as 1886, presents a different puzzle. Its whorled coat resembles the severe phenotype produced by eliminating PCP throughout the skin. Yet the trait is dominant and the animals are otherwise healthy, without the neural tube defects typically associated with PCP disruption. Together, these variants capture two distinct ways the PCP pathway can be altered: rosette changes how the PCP axis is oriented in a specific region, while the Abyssinian guinea pig disrupts PCP function in the skin through a mechanism distinct from conventional loss of function. Mapping these variants will reveal novel mechanisms controlling PCP organization across tissues.

Abyssinian guinea pig image provided by Martha Panda.

PCP in lymphatic network development

The lymphatic network is essential for maintaining fluid balance, absorbing dietary fats, and transporting immune cells throughout the body. Our collaborator, Dr. Sarah Sheppard at the National Institutes of Health, identified variants in a core PCP gene in families affected by non-immune hydrops fetalis. This severe condition, in which fluid accumulates in the developing fetus, is associated with high fetal mortality, and its genetic causes remain poorly understood. Because PCP directs the cell rearrangements that form lymphatic valves, a structure that ensures unidirectional fluid flow, these variants may impact lymphatic network function. We are using a mouse model to determine how PCP-dependent cell behaviors shape the lymphatic network. By connecting human genetics to developmental mechanisms, this work aims to improve the diagnosis, prognosis, and care of individuals with lymphatic disease.

PCP in corneal homeostasis

The cornea, the transparent outer surface of the eye, continuously renews itself throughout life. New cells arise at the outer edge of the tissue and migrate inward toward the center, replacing cells that are lost from the surface. This raises a fascinating question: how do cells in a circular tissue communicate directional information to guide centripetal migration? We found that PCP is organized across the corneal epithelium in a distinctive geometric pattern that makes it a strong candidate for guiding these collective behaviors. We are now investigating how PCP coordinates inward migration of epithelial cells to maintain a healthy, transparent cornea throughout life.