Flattop regulates basal body docking and positioning in mono- and multiciliated cells.

Moritz Gegg,Stefan Hasenoeder,Michaela Aichler,Claude Van Campenhout,Heiko Lickert,Axel Walch,Seth G N Grant,Anika Böttcher,Ingo Burtscher

doi:10.7554/elife.03842

Moritz Gegg, Stefan Hasenoeder + Show 7 more

Open Access

https://doi.org/10.7554/elife.03842

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Abstract

Planar cell polarity (PCP) regulates basal body (BB) docking and positioning during cilia formation, but the underlying mechanisms remain elusive. In this study, we investigate the uncharacterized gene Flattop (Fltp) that is transcriptionally activated during PCP acquisition in ciliated tissues. Fltp knock-out mice show BB docking and ciliogenesis defects in multiciliated lung cells. Furthermore, Fltp is necessary for kinocilium positioning in monociliated inner ear hair cells. In these cells, the core PCP molecule Dishevelled 2, the BB/spindle positioning protein Dlg3, and Fltp localize directly adjacent to the apical plasma membrane, physically interact and surround the BB at the interface of the microtubule and actin cytoskeleton. Dlg3 and Fltp knock-outs suggest that both cooperatively translate PCP cues for BB positioning in the inner ear. Taken together, the identification of novel BB/spindle positioning components as potential mediators of PCP signaling might have broader implications for other cell types, ciliary disease, and asymmetric cell division.

Highlights

The conserved Planar cell polarity (PCP) signaling pathway regulates the orientation of cells and organelles within the plane of an epithelium and is crucially important for developmental patterning as well as organ morphogenesis, homeostasis, and physiology (Seifert and Mlodzik, 2007; Wang and Nathans, 2007; Peng and Axelrod, 2012; Wallingford, 2012)
The murine Fltp gene consists of six exons and the spliced mRNA codes for an open-reading frame (ORF) of 567 nucleotides that translates into a protein of 189 amino acids (Figure 1B,C)
An alignment of the proteins of different species reveals a high conservation during evolution as well as an N-terminal SH3 binding domain and a C-terminal proline-rich repeat (PRR) (Figure 1C)

Summary

Introduction

The conserved PCP signaling pathway regulates the orientation of cells and organelles within the plane of an epithelium and is crucially important for developmental patterning as well as organ morphogenesis, homeostasis, and physiology (Seifert and Mlodzik, 2007; Wang and Nathans, 2007; Peng and Axelrod, 2012; Wallingford, 2012). Core PCP molecules including Van Gogh-like (Vangl1-2), Cadherin EGF LAG seven-pass G-type receptor (Celsr1-3), Frizzled (Fzd3, 6), Dishevelled (Dvl1-3), and Prickle (Pk1-2) are localized asymmetrically at the cell cortex to provide polarity information for morphogenesis and oriented cell division. Significant progress has been made in understanding the asymmetric core PCP localization in vertebrates but it is less clear how this regulates cytoskeletal rearrangements that drive morphogenesis via tissue specific downstream effector molecules (Wallingford, 2012). The identification of novel PCP effectors that indicate pathway activity and mediate signaling and/or morphogenesis will be the key to unravel the function of this molecular pathway in development and disease.

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