MIM regulates vertebrate neural tube closure

Liu, Wei; Komiya, Yuko; Mezzacappa, Courtney; Khadka, Deepak; Runnels, Loren W.; Habas, Raymond

doi:10.1242/dev.058800

Cited by 29 publications

(24 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The presence of bottle cells and apical-basal cell lengthening are common features of folding epithelial sheets as seen in gastrulation in Xenopus (24, 25), neural tube bending (26,27), optic vesicle formation (28), and Drosophila salivary gland development (29). Consistent with these models, at the site of new bud formation the lung epithelium thickens and adopts a pseudostratified morphology, suggesting that the epithelial thickening is the result of epithelial cell lengthening (Fig.…”

Section: Formation Of New Branch Points Requires Epithelial Thickeninmentioning

confidence: 60%

Wnt ligand/Frizzled 2 receptor signaling regulates tube shape and branch-point formation in the lung through control of epithelial cell shape

Kadzik¹,

Cohen

Morley³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

102

View full text Add to dashboard Cite

Changing the morphology of a simple epithelial tube to form a highly ramified branching network requires changes in cell behavior that lead to tissue-wide changes in organ shape. How epithelial cells in branched organs modulate their shape and behavior to promote bending and sculpting of the epithelial sheet is not well understood, and the mechanisms underlying this process remain obscure. We show that the Wnt receptor Frizzled 2 (Fzd2) is required for domain branch formation during the initial establishment of the respiratory tree. Live imaging and transcriptome analysis of lung-branching morphogenesis demonstrate that Fzd2 promotes changes in epithelial cell length and shape. These changes in cell morphology deform the developing epithelial tube to generate and maintain new domain branches. Fzd2 controls branch formation and the shape of the epithelial tube by regulating Rho signaling and by the localization of phospho-myosin light chain 2, in turn controlling the changes in the shape of epithelial cells during morphogenesis. This study demonstrates the importance of Wnt/Fzd2 signaling in promoting and maintaining changes in epithelial cell shape that affect development of a branching network. D evelopment of many epithelial-derived organs requires a process of bending, folding, and reorganization of a primitive epithelial sheet or tube to generate a functional 3D organ. The mammalian lung is derived from a simple endoderm tube through a complex series of morphological changes that generates the highly arborized airways required for postnatal respiration. In humans, the first 16 generations of branching are thought to be genetically hard-wired; this notion is supported by work on mouse lungs showing that the branching pattern across multiple mouse strains is highly reproducible (1, 2). Despite such insight, little is understood about the genetic control of the molecular and cellular mechanisms underlying branching morphogenesis in the lung.The epithelial cells that line tubular branching networks can be thought of as a large planar epithelial surface that must undergo changes in cell morphology in specific subregions for proper branch formation to occur. Several pathways, including the Wnt signaling pathway, have been implicated in regulating epithelial cell behavior in a plane. Although the canonical Wnt signaling pathway regulates gene expression through nuclear translocation of β-catenin and its subsequent coactivation of LEF/TCF transcription factors, noncanonical Wnt signaling involves a less well-defined signaling network that leads to alterations in epithelial cell shape and cytoskeletal structure. Noncanonical Wnt signaling is known to regulate changes in epithelial cell shape in convergent-extension movements (3, 4) and bending of the neural plate (5), but whether this pathway regulates the development of branched organs is unknown.In the current study we show that the Wnt receptor Frizzled 2 (Fzd2) plays a key role in regulating the epithelial cell behavior and tube morphology necessary for formation...

show abstract

Section: Formation Of New Branch Points Requires Epithelial Thickeninmentioning

confidence: 60%

Wnt ligand/Frizzled 2 receptor signaling regulates tube shape and branch-point formation in the lung through control of epithelial cell shape

Kadzik¹,

Cohen

Morley³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

102

View full text Add to dashboard Cite

show abstract

“…Single or combined mutations in mouse PCP signaling genes, such as Celsr1 (Curtin et al, 2003), Dvl1/2/3 (Etheridge et al, 2008;Hamblet et al, 2002;Wang et al, 2006a), Fzd3/6 (Wang et al, 2006b, Ptk7 (Lu et al, 2004), Scrib and Vangl2 (Kibar et al, 2001;Murdoch et al, 2001), will lead to the failure of initial neural tube closure and result in severe NTDs. The PCP-related Daam1-binding protein MIM is required for neural tube closure in Xenopus (Liu et al, 2011). Among these genes, Fzds and Dvls also act upstream of β-catenin in the canonical Wnt pathway.…”

Section: Co-regulation Of Cdx2 By β-Catenin and Pax3 During Neurulationmentioning

confidence: 99%

β-catenin regulates Pax3 and Cdx2 for caudal neural tube closure and elongation

et al. 2014

View full text Add to dashboard Cite

Non-canonical Wnt/planar cell polarity (PCP) signaling plays a primary role in the convergent extension that drives neural tube closure and body axis elongation. PCP signaling gene mutations cause severe neural tube defects (NTDs). However, the role of canonical Wnt/β-catenin signaling in neural tube closure and NTDs remains poorly understood. This study shows that conditional gene targeting of β-catenin in the dorsal neural folds of mouse embryos represses the expression of the homeobox-containing genes Pax3 and Cdx2 at the dorsal posterior neuropore (PNP), and subsequently diminishes the expression of the Wnt/β-catenin signaling target genes T, Tbx6 and Fgf8 at the tail bud, leading to spina bifida aperta, caudal axis bending and tail truncation. We demonstrate that Pax3 and Cdx2 are novel downstream targets of Wnt/β-catenin signaling. Transgenic activation of Pax3 cDNA can rescue the closure defect in the β-catenin mutants, suggesting that Pax3 is a key downstream effector of β-catenin signaling in the PNP closure process. Cdx2 is known to be crucial in posterior axis elongation and in neural tube closure. We found that Cdx2 expression is also repressed in the dorsal PNPs of Pax3-null embryos. However, the ectopically activated Pax3 in the β-catenin mutants cannot restore Cdx2 mRNA in the dorsal PNP, suggesting that the presence of both β-catenin and Pax3 is required for regional Cdx2 expression. Thus, β-catenin signaling is required for caudal neural tube closure and elongation, acting through the transcriptional regulation of key target genes in the PNP.

show abstract

“…Physical interaction between MTSS1 and Rac has been documented earlier; to the best of our knowledge, however, RhoA-MTSS1 engagement has previously not been reported. While these data are supported by observations from other cell lines where ectopic expression of MTSS1 or its I-BAR domain results in reduction of stress fibers 35 , a hallmark phenotype for RhoA inactivation 62 , they do not exclude additional indirect Rac and RhoA regulation through MTSS1 by affecting the geometry or lipid distribution of the leading edge plasma membrane through its I-BAR domain 26 or by altering the structure of the actin cytoskeleton through its interactions with cortactin or Daam1 formin 63,64 . It is also interesting to note that in contrast to earlier reports about MTSS1 to activate Rac 37 , but consistent with Rac's dispensability for I-BAR-induced filopodia formation 34 , we observed a reduction of Rac activity in HMEL cells upon MTSS1 expression.…”

Section: Discussionmentioning

confidence: 67%

MTSS1 is a metastasis driver in a subset of human melanomas

et al. 2014

View full text Add to dashboard Cite

In cancers with a highly altered genome, distinct genetic alterations drive subsets rather than the majority of individual tumours. Here we use a sequential search across human tumour samples for transcript outlier data points with associated gene copy number variations that correlate with patient's survival to identify genes with pro-invasive functionality. Employing loss and gain of function approaches in vitro and in vivo, we show that one such gene, MTSS1, promotes the ability of melanocytic cells to metastasize and engages actin dynamics via Rho-GTPases and cofilin in this process. Indeed, high MTSS1 expression defines a subgroup of primary melanomas with unfavourable prognosis. These data underscore the biological, clinical and potential therapeutic implications of molecular subsets within genetically complex cancers.

show abstract

MIM regulates vertebrate neural tube closure

Cited by 29 publications

References 50 publications

Wnt ligand/Frizzled 2 receptor signaling regulates tube shape and branch-point formation in the lung through control of epithelial cell shape

Wnt ligand/Frizzled 2 receptor signaling regulates tube shape and branch-point formation in the lung through control of epithelial cell shape

β-catenin regulates Pax3 and Cdx2 for caudal neural tube closure and elongation

MTSS1 is a metastasis driver in a subset of human melanomas

Contact Info

Product

Resources

About