Seven-Pass Transmembrane Cadherins: Roles and Emerging Mechanisms in Axonal and Dendritic Patterning

The Flamingo/Celsr seven-transmembrane cadherins represent a conserved subgroup of the cadherin superfamily involved in multiple aspects of development. In the developing nervous system, Fmi/Celsr control axonal blueprint and dendritic morphogenesis from invertebrates to mammals. As expected from their molecular structure, seven-transmembrane cadherins can induce cell–cell homophilic interactions but also intracellular signaling. Fmi/Celsr is known to regulate planar cell polarity (PCP) through interactions with PCP proteins. In the nervous system, Fmi/Celsr can function in collaboration with or independently of other PCP genes. Here, we focus on recent studies which show that seven-transmembrane cadherins use distinct molecular mechanisms to achieve diverse functions in the development of the nervous system

A role for core planar polarity proteins in cell contact-mediated orientation of planar cell division across the mammalian embryonic skin

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. © The Author(s) 2017. Supplementary information accompanies this paper at doi:10.1038/s41598-017-01971-2.The question of how cell division orientation is determined is fundamentally important for understanding tissue and organ shape in both healthy or disease conditions. Here we provide evidence for cell contact-dependent orientation of planar cell division in the mammalian embryonic skin. We propose a model where the core planar polarity proteins Celsr1 and Frizzled-6 (Fz6) communicate the long axis orientation of interphase basal cells to neighbouring basal mitoses so that they align their horizontal division plane along the same axis. The underlying mechanism requires a direct, cell surface, planar polarised cue, which we posit depends upon variant post-translational forms of Celsr1 protein coupled to Fz6. Our hypothesis has parallels with contact-mediated division orientation in early C. elegans embryos suggesting functional conservation between the adhesion-GPCRs Celsr1 and Latrophilin-1. We propose that linking planar cell division plane with interphase neighbour long axis geometry reinforces axial bias in skin spreading around the mouse embryo body.Peer reviewe

DETECTION AND CHARACTERIZATION OF 6 NOVEL PROTEIN-S (PROS) GENE LESIONS - EVALUATION OF RT-PCR AS A MUTATION SCREENING STRATEGY

The molecular genetic analysis of protein S deficiency has been hampered by the complexity of the protein S (PROS) gene and by the existence of a homologous pseudogene. In an attempt to overcome these problems, a reverse transcript-polymerase chain reaction (RT-PCR) mutation screening procedure was developed. However, the application of this mRNA-based strategy to the detection of gene lesions causing heterozygous type I protein S deficiency appears limited owing to the high proportion of patients exhibiting absence of mRNA derived from the mutation-bearing allele ("allelic exclusion"). Nevertheless, this strategy remains extremely effective for rapid mutation detection in type II/III protein S deficiency. Using the RT-PCR technique, a G-to-A transition was detected at position +1 of the exon IV donor splice site, which was associated with type I deficiency and resulted in both exon skipping and cryptic splice site utilization. No abnormal protein S was detected in plasma from this patient. A missense mutation (Asn 217 to Ser), which may interfere with calcium binding, was also detected in exon VIII in a patient with type III protein S deficiency. A further three PROS gene lesions were detected in three patients with type I deficiency by direct sequencing of exon-containing genomic PCR fragments: a single base-pair (bp) deletion in exon XIV, a 2-bp deletion in exon VIII, and a G0to-A transition at position -1 of the exon X donor splice site all resulted in the absence of mRNA expressed from the disease allele. Thus, the RT-PCR methodology proved effective for further analysis of the resulting protein S-deficient phenotypes. A missense mutation (Met570 to Thr) in exon XIV of a further type III-deficient proband was subsequently detected in this patient's cDNA. No PROS gene abnormalities were found in the remaining four subjects, three of whom exhibited allelic exclusion. However, the father of one such patient exhibiting allelic exclusion was subsequently shown to carry a nonsense mutation (Gly448 to Term) within exon XII

Protocadherin Celsr3 is crucial in axonal tract development.

In the embryonic CNS, the development of axonal tracts is required for the formation of connections and is regulated by multiple genetic and microenvironmental factors. Here we show that mice with inactivation of Celsr3, an ortholog of Drosophila melanogaster flamingo (fmi; also known as starry night, stan) that encodes a seven-pass protocadherin, have marked, selective anomalies of several major axonal fascicles, implicating protocadherins in axonal development in the mammalian CNS for the first time. In flies, fmi controls planar cell polarity (PCP) in a frizzled-dependent but wingless-independent manner. The neural phenotype in Celsr3 mutant mice is similar to that caused by inactivation of Fzd3, a member of the frizzled family. Celsr3 and Fzd3 are expressed together during brain development and may act in synergy. Thus, a genetic pathway analogous to the one that controls PCP is key in the development of the axonal blueprint