Planar cell polarity effector gene Fuzzy regulates cilia formation and Hedgehog signal transduction in mouse

Abstract

Precise planar cell polarity (PCP) is critical for the development of multiple organ systems in animals. A group of core-PCP proteins are recognized to play crucial roles in convergent extension and other PCPrelated processes in mammals. However, the functions of another group of PCP-regulating proteins, the PCP-effector proteins, are yet to be fully studied. In this study, the generation and characterization of a mouse mutant for the PCP effector gene Fuzzy (Fuz) is reported. Fuz homozygous mutants are embryonically lethal, with multiple defects including neural tube defects, abnormal dorsal/ventral patterning of the spinal cord, and defective anterior/posterior patterning of the limb buds. Fuz mutants also exhibit abnormal Hedgehog (Hh) signaling and inefficient proteolytic processing of Gli3. Finally, a significant decrease in cilia was found in Fuz homozygous mutants. In conclusion, Fuz plays an important role in cilia formation, Hh signal transduction, and embryonic development in mammals. Developmental Dynamics 238:3035-3042,

Strange as it may seem: the many links between Wnt signaling, planar cell polarity, and cilia: Figure 1.

“…While Inturned and Fuzzy play clear roles in planar polarization of wing hairs in Drosophila (Lee and Adler 2002), it is not clear that they control developmental processes generally associated with PCP in vertebrates, such as CE. Knockdown of either gene leads to mild CE defects in Xenopus, but mutant mice do not display the craniorachischisis phenotype associated with mutation of core PCP genes (Park et al 2006;Gray et al 2009;Heydeck et al 2009;Zeng et al 2010). Moreover, while widespread Hh-related defects have been observed in the epidermis of Fuz mutant mice, no defects were seen in the planar polarization of hair follicles (Dai et al 2010), as may be expected from mutation of a critical PCP gene (e.g., Guo et al 2004;Devenport and Fuchs 2008).…”

“…In Xenopus, these are highly expressed in ciliated tissues, and MO-mediated knockdown results in profound defects in ciliogenesis and Hedgehog signaling (Park et al 2006). The requirement for these proteins in ciliogenesis and Hh signaling is conserved in the mouse (Gray et al 2009;Heydeck et al 2009;Dai et al 2010;Zeng et al 2010).…”

Principles of planar polarity in animal development

“…Loss of their activity in frog and in mouse has only mild effects on gastrulation, but disrupts ciliogenesis, additionally causing defects in Hh signalling due to cilia loss (Park et al, 2006;Gray et al, 2009;Heydeck et al, 2009;Kim et al, 2010;Zeng et al, 2010). Furthermore, during frog gastrulation, Frtz loss affects the ability of cells to elongate but not their polarity (Kim et al, 2010).…”

miR-219 regulates neural progenitors by dampening apical Par protein-dependent Hedgehog signaling

“…Does modulation of cilia dynamics account for modulation of Hh signaling and cell cycle exit? Mouse embryos lacking cilia are nearly devoid of Hh signaling (Huangfu et al, 2003;May et al, 2005) and mouse mutations that alter cilia formation also disrupt Hh signaling (Gray et al, 2009;Heydeck et al, 2009;Zeng et al, 2010) suggesting that regulation of ciliogenesis could have corresponding effects on Hh signaling. Zebrafish embryos that lack functions of Ift88 or Talpid3 have no primary cilia and are deficient for high-level Hh signaling but have expanded low-level signaling (Ben et al, 2011;Huang and Schier, 2009), suggesting that in zebrafish, cilia promote efficient Hh signaling.…”