Partial interchangeability of Fz3 and Fz6 in tissue polarity signaling for epithelial orientation and axon growth and guidance

Abstract

In mammals, a set of anatomically diverse polarity processesincluding axon growth and guidance, hair follicle orientation, and stereociliary bundle orientation in inner ear sensory hair cells -appear to be mechanistically related, as judged by their dependence on vertebrate homologues of core tissue polarity/planar cell polarity (PCP) genes in Drosophila. To explore more deeply the mechanistic similarities between different polarity processes, we have determined the extent to which frizzled 3 (Fz3) can rescue the hair follicle and Merkel cell polarity defects in frizzled 6-null (Fz6 −/− ) mice, and, reciprocally, the extent to which Fz6 can rescue the axon growth and guidance defects in Fz3 −/− mice. These experiments reveal full rescue of the Fz6 −/− phenotype by Fz3 and partial rescue of the Fz3 −/− phenotype by Fz6, implying that these two proteins are likely to act in a conserved manner in these two contexts. Stimulated by these observations, we searched for additional anatomical structures that exhibit macroscopic polarity and that might plausibly use Fz3 and/or Fz6 signaling. This search has revealed a hitherto unappreciated pattern of papillae on the dorsal surface of the tongue that depends, at least in part, on redundant signaling by Fz3 and Fz6. Taken together, these experiments provide compelling evidence for a close mechanistic relationship between multiple anatomically diverse polarity processes.

Patterning of papillae on the mouse tongue: A system for the quantitative assessment of planar cell polarity signaling

“…The work of Hua et al (2014) and the experiments described above, show that Frizzled and Vangl also control LP orientation on the dorsal surface of the tongue. To determine whether Celsr1 also plays a role in LP orientation, we examined flat mounts of Celsr1 -/-and Celsr1 +/-, tongues at P30 (Figure 8).…”

“…In previous work (Hua et al, 2014), LP on the dorsal surface of the tongue were visualized in whole mount preparations by genetic labeling with Keratin (K)17-GFP (Bianchi et al, 2005) or by systemic administration of the fixable dye AM4-65. More recently, we observed that the tongue epithelium of mice that are >2-3 weeks of age exhibit endogenous fluorescence that can be used to visualize LP.…”

“…It is interesting to compare the patterning of hair follicles and LP and the effects of PCP gene mutations on these two epidermal derivatives (Wang et al, 2006a;Hua et al, 2014;Chang et al, 2016;this work). On hair-covered regions of skin and on the dorsal surface of the tongue, WT mice develop stereotyped patterns of hair follicles and LP that show a high degree of order on both local and global scales.…”

“…Hua et al (2014) demonstrated that the orientations of LP are regulated by PCP genes Fz3 and Fz6. Eliminating Fz3 selectively in the epidermis with a Keratin14-Cre transgene (Fz3 CKO/-;K14-Cre; CKO, conditional knockout) or eliminating Fz6 constitutively (Fz6 -/-) did not alter the LP pattern, but combining both of these genetic alterations (Fz3 CKO/-;Fz6 -/-;K14-Cre) produced a mild disruption in the local order of LP, primarily in the anterior of the tongue.…”

Frizzled Receptors in Development and Disease

“…Fz3 −/− ;Fz6 −/− embryos reveal redundant functions in neural tube closure and in rotationally orientating the kinocilium/stereociliary bundle complex on the apical face of inner ear sensory hair cells (Wang, Guo, & Nathans, 2006). Additionally, epidermis-specific double knockout of Fz3 and Fz6 (in K14-Cre; Fz3 CKO/CKO ;Fz6 −/− mice) reveals a redundant role for these genes in orienting the filiform papillae on the dorsal surface of the tongue (Hua, Chang, et al, 2014). Stimulated by the partial redundancy of Fz3 and Fz6 , Hua, Chang, et al (2014) asked whether this redundancy can be extended to other tissues by enlarging the domains of Fz3 and Fz6 gene expression.…”