Planar polarization in embryonic epidermis orchestrates global asymmetric morphogenesis of hair follicles

Abstract

Mammalian body hairs align along the anterior-posterior axis and offer a striking but poorly understood example of global cell polarization, a phenomenon known as planar cell polarity (PCP). We’ve discovered that during embryogenesis, dramatic changes in cell shape and cytoskeletal polarization occur as nascent hair follicles (HFs) become anteriorly angled, morphologically polarized and molecularly compartmentalized along the A–P axis. Interestingly, HF initiation coincides with asymmetric redistribution of Vangl2, Celsr1 and Fzd6 within the embryonic epidermal basal layer. Moreover, loss of function mutations in Vangl2 and Celsr1 unveil their essential role in HF polarization and orientation, which develop in part, through nonautonomous mechanisms. Vangl2 and Celsr1 are mutually required for their planar localization in vivo, and physically associate in a complex in vitro. Finally, we provide evidence in vitro that homotypic interactions of Celsr1 intercellularly are required to recruit Vangl2 and Fzd6 to sites of cell-cell contact.

Far from solved: A perspective on what we know about early mechanisms of left–right asymmetry

“…We note that planar cell polarity (PCP) and LR orientation have many similarities, including the need to amplify a patterning signal across large numbers of cells, and the ability of proteins to segregate and orient themselves with respect to each other in a consistently biased manner, generating a large scale signal that originates intracellularly. PCP also enables orientation of cell polarity within the large-scale axes of a host; for example, when grafts of embryonic skin were transplanted into adults, the skin cells realigned their planar hair polarity to match that of the hosts (Devenport and Fuchs, 2008). PCP is an attractive mechanism for LR asymmetry because it can impose the initial orientation of cells or small groups of blastomeres to entire cell fields (Amonlirdviman et al, 2005), as was originally proposed in the ''LR Coordinator'' model (Hyatt and Yost, 1998).…”

Responses of hair follicle–associated structures to loss of planar cell polarity signaling

“…In mice, follicles and follicle-associated structures form on different schedules. Guard hair follicles and semicircular Merkel cell clusters are present by embryonic day (E) 16, and follicle-associated lanceolate nerve endings are present by postnatal day (P)0, but sebaceous glands and APMs develop postnatally (2,(10)(11)(12)(13).…”

“…First defined in Drosophila, PCP signaling is mediated by a core set of approximately six genes that form asymmetric cell surface complexes and convey vectorial information from cell to cell within an epithelium (14). In mice, loss-of-function mutations in Frizzled (Fz)6 or Celsr1, or the semidominant Loop-tail gain-of-function mutation in Vangl2-all homologs of core PCP genes in Drosophila-lead to aberrant hair follicle orientations (15)(16)(17)(18)(19). In Fz6 −/− mice, where this phenomenon has been most extensively studied, follicles on the back initially exhibit orientations that appear approximately random.…”

Promyelocytic leukemia bodies tether to early endosomes during mitosis

“…Alternatively, the tethering of PML bodies to early endosomes during cell division may represent a mechanism that controls faithful distribution of PML bodies to newly divided daughter cells. In agreement with this, mitotic endosomes have previously been shown to control segregation of plasma membrane-anchored surface proteins such as planar cell polarity proteins 26 and the notch-delta signaling complex. 27 Although the majority of MAPPs appeared to become anchored to early endosomes, our live cell particle tracking experiments also revealed a minor sub-population of MAPPs that becomes attached to structures near the poles of the mitotic spindle.…”