scholarly journals Endocytic recycling protein EHD1 regulates primary cilia morphogenesis and SHH signaling during neural tube development

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Sohinee Bhattacharyya ◽  
Mark A Rainey ◽  
Priyanka Arya ◽  
Bhopal C. Mohapatra ◽  
Insha Mushtaq ◽  
...  
Keyword(s):  
Neural Tube ◽  
Hedgehog Signaling ◽  
Primary Cilia ◽  
Gene Knockout ◽  
Neural Tube Closure ◽  
Endocytic Recycling ◽  
Shh Signaling ◽  
Neuronal Markers ◽  
Surface Receptors ◽  
Direct Binding

Abstract Members of the four-member C-terminal EPS15-Homology Domain-containing (EHD) protein family play crucial roles in endocytic recycling of cell surface receptors from endosomes to the plasma membrane. In this study, we show that Ehd1 gene knockout in mice on a predominantly B6 background is embryonic lethal. Ehd1-null embryos die at mid-gestation with a failure to complete key developmental processes including neural tube closure, axial turning and patterning of the neural tube. We found that Ehd1-null embryos display short and stubby cilia on the developing neuroepithelium at embryonic day 9.5 (E9.5). Loss of EHD1 also deregulates the ciliary SHH signaling with Ehd1-null embryos displaying features indicative of increased SHH signaling, including a significant downregulation in the formation of the GLI3 repressor and increase in the ventral neuronal markers specified by SHH. Using Ehd1-null MEFS we found that EHD1 protein co-localizes with the SHH receptor Smoothened in the primary cilia upon ligand stimulation. Under the same conditions, EHD1 was shown to co-traffic with Smoothened into the developing primary cilia and we identify EHD1 as a direct binding partner of Smoothened. Overall, our studies identify the endocytic recycling regulator EHD1 as a novel regulator of the primary cilium-associated trafficking of Smoothened and Hedgehog signaling.

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

2020 ◽  
Author(s):  
Eric R. Brooks ◽  
Mohammed T. Islam ◽  
Kathryn V. Anderson ◽  
Jennifer A. Zallen
Keyword(s):  
Sonic Hedgehog ◽  
Neural Tube ◽  
Hedgehog Signaling ◽  
Structural Changes ◽  
Neural Tube Closure ◽  
Mammalian Brain ◽  
Shh Signaling ◽  
Apical Constriction ◽  
Cell Remodeling ◽  
Tube Closure

AbstractNeural 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.

scholarly journals Erratum: Corrigendum: Endocytic recycling protein EHD1 regulates primary cilia morphogenesis and SHH signaling during neural tube development

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Sohinee Bhattacharyya ◽  
Mark A. Rainey ◽  
Priyanka Arya ◽  
Bhopal C. Mohapatra ◽  
Insha Mushtaq ◽  
...  
Keyword(s):  
Neural Tube ◽  
Primary Cilia ◽  
Endocytic Recycling ◽  
Shh Signaling ◽  
Neural Tube Development

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

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Eric R Brooks ◽  
Mohammed Tarek Islam ◽  
Kathryn V Anderson ◽  
Jennifer A Zallen
Keyword(s):  
Sonic Hedgehog ◽  
Neural Tube ◽  
Hedgehog Signaling ◽  
Structural Changes ◽  
Neural Tube Closure ◽  
Mammalian Brain ◽  
Shh Signaling ◽  
Apical Constriction ◽  
Cell Remodeling ◽  
Tube Closure

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 flat 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.

scholarly journals Ciliary and extraciliary Gpr161 pools repress hedgehog signaling in a tissue-specific manner

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Sun-Hee Hwang ◽  
Bandarigoda N Somatilaka ◽  
Kevin White ◽  
Saikat Mukhopadhyay
Keyword(s):  
G Protein ◽  
Neural Tube ◽  
Hedgehog Signaling ◽  
Primary Cilia ◽  
Camp Signaling ◽  
Tissue Specific ◽  
Specific Manner ◽  
G Protein Coupled ◽  
Ciliary Localization

The role of compartmentalized signaling in primary cilia during tissue morphogenesis is not well understood. The cilia-localized G-protein-coupled receptor—Gpr161 represses hedgehog pathway via cAMP signaling. We engineered a knock-in at Gpr161 locus in mice to generate a variant (Gpr161mut1), which was ciliary localization defective but cAMP signaling competent. Tissue phenotypes from hedgehog signaling depend on downstream bifunctional Gli transcriptional factors functioning as activators/repressors. Compared to knockout (ko), Gpr161mut1/ko had delayed embryonic lethality, moderately increased hedgehog targets and partially down-regulated Gli3-repressor. Unlike ko, the Gpr161mut1/ko neural tube did not show Gli2-activator-dependent expansion of ventral-most progenitors. Instead, the intermediate neural tube showed progenitor expansion that depends on loss of Gli3-repressor. Increased extraciliary receptor (Gpr161mut1/mut1) prevented ventralization. Morphogenesis in limb buds and midface requires Gli-repressor; these tissues in Gpr161mut1/mut1 manifested hedgehog hyperactivation phenotypes—polydactyly and midfacial widening. Thus, ciliary and extraciliary Gpr161 pools likely establish tissue-specific Gli-repressor thresholds in determining morpho-phenotypic outcomes.

Sonic hedgehog and the molecular regulation of mouse neural tube closure

Development ◽  
2002 ◽  
Vol 129 (10) ◽  
pp. 2507-2517 ◽  
Author(s):  
Patricia Ybot-Gonzalez ◽  
Patricia Cogram ◽  
Dianne Gerrelli ◽  
Andrew J. Copp
Keyword(s):  
Sonic Hedgehog ◽  
Neural Tube ◽  
Hedgehog Signaling ◽  
Neural Plate ◽  
Neural Tube Closure ◽  
Molecular Regulation ◽  
Sonic Hedgehog Signaling ◽  
Surface Ectoderm ◽  
Necessary And Sufficient ◽  
Tube Closure

Neural tube closure is a fundamental embryonic event whose molecular regulation is poorly understood. As mouse neurulation progresses along the spinal axis, there is a shift from midline neural plate bending to dorsolateral bending. Here, we show that midline bending is not essential for spinal closure since, in its absence, the neural tube can close by a ‘default’ mechanism involving dorsolateral bending, even at upper spinal levels. Midline and dorsolateral bending are regulated by mutually antagonistic signals from the notochord and surface ectoderm. Notochordal signaling induces midline bending and simultaneously inhibits dorsolateral bending. Sonic hedgehog is both necessary and sufficient to inhibit dorsolateral bending, but is neither necessary nor sufficient to induce midline bending, which seems likely to be regulated by another notochordal factor. Attachment of surface ectoderm cells to the neural plate is required for dorsolateral bending, which ensures neural tube closure in the absence of sonic hedgehog signaling.

Zebrafishsmoothenedfunctions in ventral neural tube specification and axon tract formation

Development ◽  
2001 ◽  
Vol 128 (18) ◽  
pp. 3497-3509 ◽  
Author(s):  
Zoltán M. Varga ◽  
Angel Amores ◽  
Katharine E. Lewis ◽  
Yi-Lin Yan ◽  
John H. Postlethwait ◽  
...  
Keyword(s):  
Sonic Hedgehog ◽  
Neural Tube ◽  
Hedgehog Signaling ◽  
Floor Plate ◽  
Slow Muscle ◽  
Pituitary Cells ◽  
Shh Signaling ◽  
Ventral Neural Tube ◽  
Hypothalamic Cells

Sonic hedgehog (Shh) signaling patterns many vertebrate tissues. shh mutations dramatically affect mouse ventral forebrain and floor plate but produce minor defects in zebrafish. Zebrafish have two mammalian Shh orthologs, sonic hedgehog and tiggy-winkle hedgehog, and another gene, echidna hedgehog, that could have overlapping functions. To examine the role of Hedgehog signaling in zebrafish, we have characterized slow muscle omitted (smu) mutants. We show that smu encodes a zebrafish ortholog of Smoothened that transduces Hedgehog signals. Zebrafish smoothened is expressed maternally and zygotically and supports specification of motoneurons, pituitary cells and ventral forebrain. We propose that smoothened is required for induction of lateral floor plate and a subpopulation of hypothalamic cells and for maintenance of medial floor plate and hypothalamic cells.

scholarly journals Sonic Hedgehog Signaling in Organogenesis, Tumors, and Tumor Microenvironments

2020 ◽  
Vol 21 (3) ◽  
pp. 758 ◽  
Author(s):  
Kuo-Shyang Jeng ◽  
Chiung-Fang Chang ◽  
Shu-Sheng Lin
Keyword(s):  
Tumor Microenvironment ◽  
Signaling Pathway ◽  
Sonic Hedgehog ◽  
Cancer Progression ◽  
Hedgehog Signaling ◽  
Primary Cilia ◽  
Tumor Development ◽  
Sonic Hedgehog Signaling ◽  
Shh Signaling ◽  
Tumor Microenvironments

During mammalian embryonic development, primary cilia transduce and regulate several signaling pathways. Among the various pathways, Sonic hedgehog (SHH) is one of the most significant. SHH signaling remains quiescent in adult mammalian tissues. However, in multiple adult tissues, it becomes active during differentiation, proliferation, and maintenance. Moreover, aberrant activation of SHH signaling occurs in cancers of the skin, brain, liver, gallbladder, pancreas, stomach, colon, breast, lung, prostate, and hematological malignancies. Recent studies have shown that the tumor microenvironment or stroma could affect tumor development and metastasis. One hypothesis has been proposed, claiming that the pancreatic epithelia secretes SHH that is essential in establishing and regulating the pancreatic tumor microenvironment in promoting cancer progression. The SHH signaling pathway is also activated in the cancer stem cells (CSC) of several neoplasms. The self-renewal of CSC is regulated by the SHH/Smoothened receptor (SMO)/Glioma-associated oncogene homolog I (GLI) signaling pathway. Combined use of SHH signaling inhibitors and chemotherapy/radiation therapy/immunotherapy is therefore key in targeting CSCs.

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