Hedgehog Signaling Regulates Epithelial Morphogenesis to Position the Ventral Embryonic Midline

Arraf, Alaa A.; Yelin, Ronit; Reshef, Inbar; Jadon, Julian; Abboud, Manar; Zaher, Mira; Schneider, Jenny; Vladimirov, Fanny K.; Schultheiss, Thomas M.

doi:10.1016/j.devcel.2020.04.016

Cited by 18 publications

(12 citation statements)

References 69 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Knockdown of RhoU expression was described to cause abnormal flattening of the mouse foregut epithelium, with loss of the sub-apical cortical actin domain [ 70 ]. Arraff and colleagues [ 73 ] found that interfering with RhoU activity caused epithelial flattening as well as disruptions in the orientation of coelomic epithelial cells. RhoU has a role also in the FA turnover, in the dismantle of stress fibers and in the formation of filopodia and cell adhesion [ 70 , 74 ].…”

Section: Discussionmentioning

confidence: 99%

OVOL2 impairs RHO GTPase signaling to restrain mitosis and aggressiveness of Anaplastic Thyroid Cancer

Gugnoni

Manzotti

Vitale

et al. 2022

J Exp Clin Cancer Res

View full text Add to dashboard Cite

Background Anaplastic Thyroid Cancer (ATC) is an undifferentiated and aggressive tumor that often originates from well-Differentiated Thyroid Carcinoma (DTC) through a trans-differentiation process. Epithelial-to-Mesenchymal Transition (EMT) is recognized as one of the major players of this process. OVOL2 is a transcription factor (TF) that promotes epithelial differentiation and restrains EMT during embryonic development. OVOL2 loss in some types of cancers is linked to aggressiveness and poor prognosis. Here, we aim to clarify the unexplored role of OVOL2 in ATC. Methods Gene expression analysis in thyroid cancer patients and cell lines showed that OVOL2 is mainly associated with epithelial features and its expression is deeply impaired in ATC. To assess OVOL2 function, we established an OVOL2-overexpression model in ATC cell lines and evaluated its effects by analyzing gene expression, proliferation, invasion and migration abilities, cell cycle, specific protein localization through immunofluorescence staining. RNA-seq profiling showed that OVOL2 controls a complex network of genes converging on cell cycle and mitosis regulation and Chromatin Immunoprecipitation identified new OVOL2 target genes. Results Coherently with its reported function, OVOL2 re-expression restrained EMT and aggressiveness in ATC cells. Unexpectedly, we observed that it caused G2/M block, a consequent reduction in cell proliferation and an increase in cell death. This phenotype was associated to generalized abnormalities in the mitotic spindle structure and cytoskeletal organization. By RNA-seq experiments, we showed that many pathways related to cytoskeleton and migration, cell cycle and mitosis are profoundly affected by OVOL2 expression, in particular the RHO-GTPase pathway resulted as the most interesting. We demonstrated that RHO GTPase pathway is the central hub of OVOL2-mediated program in ATC and that OVOL2 transcriptionally inhibits RhoU and RhoJ. Silencing of RhoU recapitulated the OVOL2-driven phenotype pointing to this protein as a crucial target of OVOL2 in ATC. Conclusions Collectively, these data describe the role of OVOL2 in ATC and uncover a novel function of this TF in inhibiting the RHO GTPase pathway interlacing its effects on EMT, cytoskeleton dynamics and mitosis.

show abstract

Section: Discussionmentioning

confidence: 99%

OVOL2 impairs RHO GTPase signaling to restrain mitosis and aggressiveness of Anaplastic Thyroid Cancer

Gugnoni

Manzotti

Vitale

et al. 2022

J Exp Clin Cancer Res

View full text Add to dashboard Cite

show abstract

“…Shh signaling has long been recognized to play an important role in controlling positional cell fates in many developing organs, including the limb, the gut, and the spinal cord ( Jessell, 2000 ; Villavicencio et al, 2000 ; McMahon et al, 2003 ; McGlinn and Tabin, 2006 ; Tickle and Towers, 2017 ; Sagner and Briscoe, 2019 ). Although the effects of Shh on cell behavior have received comparatively less attention, Shh has been shown to influence axon guidance ( Zuñiga and Stoeckli, 2017 ), cell migration ( Gordon et al, 2018 ), mesenchymal cell clustering ( Rao-Bhatia et al, 2020 ), and epithelial remodeling in mice, chicks, frogs, and flies ( Corrigall et al, 2007 ; Escudero et al, 2007 ; Nasr et al, 2019 ; Arraf et al, 2020 ). Depending on the context, proteins in the Shh family can have contrasting effects on epithelial cell behavior, promoting apical constriction in the Drosophila eye ( Corrigall et al, 2007 ; Escudero et al, 2007 ), generating short and flat cells in the neural tube ( Fournier-Thibault et al, 2009 and this work), and inducing tall, pseudostratified cells in the chick coelomic cavity ( Arraf et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

“…Although the effects of Shh on cell behavior have received comparatively less attention, Shh has been shown to influence axon guidance ( Zuñiga and Stoeckli, 2017 ), cell migration ( Gordon et al, 2018 ), mesenchymal cell clustering ( Rao-Bhatia et al, 2020 ), and epithelial remodeling in mice, chicks, frogs, and flies ( Corrigall et al, 2007 ; Escudero et al, 2007 ; Nasr et al, 2019 ; Arraf et al, 2020 ). Depending on the context, proteins in the Shh family can have contrasting effects on epithelial cell behavior, promoting apical constriction in the Drosophila eye ( Corrigall et al, 2007 ; Escudero et al, 2007 ), generating short and flat cells in the neural tube ( Fournier-Thibault et al, 2009 and this work), and inducing tall, pseudostratified cells in the chick coelomic cavity ( Arraf et al, 2020 ). An understanding of the mechanisms by which Shh signaling directs cell morphology will provide insight into how this conserved, positionally encoded molecular mechanism coordinates cell fate with three-dimensional tissue structure.…”

Section: Discussionmentioning

confidence: 99%

Sonic hedgehog signaling directs patterned cell remodeling during cranial neural tube closure

Brooks

Islam

Anderson

et al. 2020

eLife

View full text Add to dashboard Cite

Neural tube closure defects are a major cause of infant mortality, with exencephaly accounting for nearly one-third of cases. However, the mechanisms of cranial neural tube closure are not well understood. Here we show that this process involves a tissue-wide pattern of apical constriction controlled by Sonic hedgehog (Shh) signaling. Midline cells in the mouse midbrain neuroepithelium are short with large apical surfaces, whereas lateral cells are taller and undergo synchronous apical constriction, driving neural fold elevation. Embryos lacking the Shh effector Gli2 fail to produce appropriate midline cell architecture, whereas embryos with expanded Shh signaling, including the IFT-A complex mutants Ift122 and Ttc21b and embryos expressing activated Smoothened, display apical constriction defects in lateral cells. Disruption of lateral, but not midline, cell remodeling results in exencephaly. These results reveal a morphogenetic program of patterned apical constriction governed by Shh signaling that generates structural changes in the developing mammalian brain.

show abstract

“…3K). This indicates that the multilayered mesenchyme undergoes extensive compaction to transform into a two-layered epithelium and raises the possibility that the LPM may undergo a type of convergent extension during MET, wherein the layer converges (thins) in the dorsal-ventral dimension as it extends in medial-lateral and anterior-posterior axes 40 .…”

Section: Resultsmentioning

confidence: 99%

“…The wave-like nature of MET progression is seen particularly clearly when analyzing expression of the cell-cell adhesion protein N-Cadherin (N-Cad; LPM cells express N-Cad and not E-Cad 40 ). In the mesenchymal state (Fig.…”

Section: I White Arrow)mentioning

confidence: 99%

A Morphogenetic Wave that Generates Mesenchymal-to-Epithelial Transition in the Lateral Plate Mesoderm

Asleh

Zaher

Jadon

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

Most mesodermal cells undergo multiple cycles of transition between an epithelial and mesenchymal state during embryonic development. While many studies have addressed the process of epithelial-to-mesenchymal transition (EMT), comparatively less is known regarding the complementary process, mesenchymal-to-epithelial transition (MET), which is essential for organogenesis and has also been proposed to be important for cancer metastasis. The current study investigated MET using the lateral plate mesoderm (LPM) of the chick embryo as a model system. We find that MET in the LPM proceeds as a wave, which divides the LPM into distinct mesenchymal, transition, and epithelial zones. In the multilayered mesenchymal zone, many apical epithelial markers, including N-Cadherin (N-Cad), Par-3 and Zo-1, but not atypical protein kinase C (aPKC), are detected as dispersed, partially co-localizing aggregates associated with cell-cell contacts. The transition zone is characterized by the appearance of aPKC and the formation of rosette-like structures characterized by wedge-shaped cells that are apical-basal polarized, with strong co-localization of apical polarity markers, but not yet arranged into distinct epithelial sheets. The transition zone is also enriched in mitotic cells. Subsequently, the rosettes resolve into two well-defined epithelial sheets that constitute the coelomic epithelium, the lining of the internal body cavity. Prior to any overt signs of apical-basal polarity, fibronectin (FN) begins to accumulate at the future basal side of the incipient epithelium. Interference with Extracellular Matrix (ECM)-integrin signaling through disruption of focal adhesion kinase (FAK) or Talin function hindered the normal progression of the epithelialization process. Cells with disrupted FAK or Talin function retained mesenchymal-like characteristics with respect to cellular morphology and apical-basal marker distribution. We propose a two-stage process for MET in the LPM. Initially, in the polarization phase, ECM-integrin-dependent signaling imparts apical-basal polarity, culminating in the activation of aPKC, to drive cell intercalation and rosette formation. Subsequently in the resolution phase, polarized rosette cells, perhaps facilitated by the weakening of cell-cell interactions that occurs during mitosis, expand their apical surface, and spread out to form new connections laterally to their fully epithelial neighbors. This sequence of events is propagated as a wave through the LPM, thus generating an integrated coelomic epithelium.

show abstract

Hedgehog Signaling Regulates Epithelial Morphogenesis to Position the Ventral Embryonic Midline

Abstract: Highlights d Convergence of the coelomic epithelium involves cell flattening and disorganization d Hh signaling regulates coelomic epithelium morphogenesis and N-cadherin distribution d Sec5 and RhoU function downstream of Hh d Hh signaling controls dorsal mesentery midline positioning

Cited by 18 publications

References 69 publications

OVOL2 impairs RHO GTPase signaling to restrain mitosis and aggressiveness of Anaplastic Thyroid Cancer

OVOL2 impairs RHO GTPase signaling to restrain mitosis and aggressiveness of Anaplastic Thyroid Cancer

Sonic hedgehog signaling directs patterned cell remodeling during cranial neural tube closure

A Morphogenetic Wave that Generates Mesenchymal-to-Epithelial Transition in the Lateral Plate Mesoderm

Contact Info

Product

Resources

About