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1.
Head Neck Pathol ; 18(1): 56, 2024 Jun 25.
Article in English | MEDLINE | ID: mdl-38916683

ABSTRACT

BACKGROUND: Angiosarcoma is a sarcoma that occurs in a range of tissue types, and only rarely in the salivary glands, showing a predilection for the parotid glands of older patients. Preoperative diagnosis may be challenging, especially on cytology, with significant morphological overlap with high-grade primary salivary gland carcinomas. The molecular alterations of this rare salivary gland neoplasm are also not well-characterized. METHODS AND RESULTS: We present a case of right submandibular gland swelling in a 73-year-old male. On fine needle aspiration, including immunohistochemical stains on cell block, the tumor was initially diagnosed as poorly differentiated carcinoma. Resection of the submandibular gland revealed epithelioid angiosarcoma. We performed molecular work-up of the tumor, utilizing targeted next-generation sequencing, DNA methylation profiling and fluorescence in-situ hybridization. Histopathologic assessment revealed an infiltrative tumor comprising solid sheets of epithelioid cells. The tumor cells formed haphazardly anastomosing vascular channels with intracytoplasmic lumina containing red blood cells. On immunohistochemistry, the tumor cells were positive for CD31, CD34 and ERG. Approximately 40% of the tumor cells showed nuclear expression of GATA3. A pathogenic TP53 R267W mutation was detected on next-generation sequencing. DNA methylation analysis did not cluster the tumor with any known sarcoma type. Copy number analysis showed possible MYC amplification and CDKN2A losses, although only the latter was confirmed on fluorescence in-situ hybridization. CONCLUSION: Epithelioid angiosarcoma is an important differential diagnosis to high-grade salivary gland carcinoma. In particular, GATA3 expression may be encountered in both angiosarcoma and high-grade salivary gland carcinomas and cause diagnostic confusion. Identification of TP53 mutations and CDKN2A losses suggest shared oncogenic pathways with soft tissue angiosarcomas, and should be further investigated.


Subject(s)
Hemangiosarcoma , Submandibular Gland Neoplasms , Humans , Male , Aged , Hemangiosarcoma/genetics , Hemangiosarcoma/pathology , Hemangiosarcoma/diagnosis , Submandibular Gland Neoplasms/pathology , Submandibular Gland Neoplasms/genetics , Submandibular Gland Neoplasms/diagnosis , Biomarkers, Tumor/analysis , Biomarkers, Tumor/genetics , Cytology
3.
Nat Genet ; 54(1): 62-72, 2022 01.
Article in English | MEDLINE | ID: mdl-34903892

ABSTRACT

The vertebrate left-right axis is specified during embryogenesis by a transient organ: the left-right organizer (LRO). Species including fish, amphibians, rodents and humans deploy motile cilia in the LRO to break bilateral symmetry, while reptiles, birds, even-toed mammals and cetaceans are believed to have LROs without motile cilia. We searched for genes whose loss during vertebrate evolution follows this pattern and identified five genes encoding extracellular proteins, including a putative protease with hitherto unknown functions that we named ciliated left-right organizer metallopeptide (CIROP). Here, we show that CIROP is specifically expressed in ciliated LROs. In zebrafish and Xenopus, CIROP is required solely on the left side, downstream of the leftward flow, but upstream of DAND5, the first asymmetrically expressed gene. We further ascertained 21 human patients with loss-of-function CIROP mutations presenting with recessive situs anomalies. Our findings posit the existence of an ancestral genetic module that has twice disappeared during vertebrate evolution but remains essential for distinguishing left from right in humans.


Subject(s)
Biological Evolution , Body Patterning , Gene Regulatory Networks , Metalloproteases , Animals , Humans , Body Patterning/genetics , Body Patterning/physiology , Cilia/genetics , Loss of Function Mutation , Metalloproteases/genetics , Metalloproteases/physiology , Proteins/genetics , Proteins/physiology , Vertebrates/genetics
4.
Cell Rep ; 37(1): 109775, 2021 10 05.
Article in English | MEDLINE | ID: mdl-34610312

ABSTRACT

Motile cilia defects impair cerebrospinal fluid (CSF) flow and can cause brain and spine disorders. The development of ciliated cells, their impact on CSF flow, and their function in brain and axial morphogenesis are not fully understood. We have characterized motile ciliated cells within the zebrafish brain ventricles. We show that the ventricles undergo restructuring through development, involving a transition from mono- to multiciliated cells (MCCs) driven by gmnc. MCCs co-exist with monociliated cells and generate directional flow patterns. These ciliated cells have different developmental origins and are genetically heterogenous with respect to expression of the Foxj1 family of ciliary master regulators. Finally, we show that cilia loss from the tela choroida and choroid plexus or global perturbation of multiciliation does not affect overall brain or spine morphogenesis but results in enlarged ventricles. Our findings establish that motile ciliated cells are generated by complementary and sequential transcriptional programs to support ventricular development.


Subject(s)
Brain/metabolism , Cilia/metabolism , Ependyma/metabolism , Animals , Animals, Genetically Modified/metabolism , Brain/cytology , Brain/pathology , Cell Lineage , Cerebrospinal Fluid/physiology , Cilia/pathology , Embryo, Nonmammalian/metabolism , Ependyma/cytology , Ependyma/pathology , Forkhead Transcription Factors/genetics , Forkhead Transcription Factors/metabolism , Gene Editing , Morphogenesis , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Spine/growth & development , Spine/metabolism , Telencephalon/cytology , Telencephalon/metabolism , Telencephalon/pathology , Tubulin/metabolism , Zebrafish , Zebrafish Proteins/genetics , Zebrafish Proteins/metabolism
5.
Dev Biol ; 465(2): 168-177, 2020 09 15.
Article in English | MEDLINE | ID: mdl-32735790

ABSTRACT

Multiciliated cells (MCCs) differentiate hundreds of motile cilia that beat to drive fluid movement over various kinds of epithelia. In Xenopus, mice and human, the coiled-coil containing protein Mcidas (Mci) has been shown to be a key transcriptional regulator of MCC differentiation. We have examined Mci function in the zebrafish, another model organism that is widely used to study ciliary biology. We show that zebrafish mci is expressed specifically in the developing MCCs of the kidney tubules, but surprisingly, not in those of the nasal placodes. Mci proteins lack a DNA binding domain and associate with the cell-cycle transcription factors E2f4/5 for regulating MCC-specific gene expression. We found that while the zebrafish Mci protein can complex with the E2f family members, its sequence as well as the requirement and sufficiency for MCC differentiation has diverged significantly from Mci homologues of the tetrapods. We also provide evidence that compared to Gmnc, another related coiled-coil protein that has recently been shown to regulate MCC development upstream of Mci, the Mci protein originated later within the vertebrate lineage. Based on these data, we argue that in contrast to Gmnc, which has a vital role in the genetic circuitry that drives MCC formation, the requirement of Mci, at least in the zebrafish, is not obligatory.


Subject(s)
Cilia , Gene Expression Regulation, Developmental , Kidney Tubules/embryology , Signal Transduction , Transcription Factors , Zebrafish Proteins , Zebrafish , Animals , Cell Cycle , Cilia/genetics , Cilia/metabolism , Transcription Factors/genetics , Transcription Factors/metabolism , Zebrafish/embryology , Zebrafish/genetics , Zebrafish Proteins/genetics , Zebrafish Proteins/metabolism
6.
Development ; 146(6)2019 03 15.
Article in English | MEDLINE | ID: mdl-30877126

ABSTRACT

Motile cilia on multiciliated cells (MCCs) function in fluid clearance over epithelia. Studies with Xenopus embryos and individuals with the congenital respiratory disorder reduced generation of multiple motile cilia (RGMC), have implicated the nuclear protein MCIDAS (MCI), in the transcriptional regulation of MCC specification and differentiation. Recently, a paralogous protein, geminin coiled-coil domain containing (GMNC), was also shown to be required for MCC formation. Surprisingly, in contrast to the presently held view, we find that Mci mutant mice can specify MCC precursors. However, these precursors cannot produce multiple basal bodies, and mature into single ciliated cells. We identify an essential role for MCI in inducing deuterosome pathway components for the production of multiple basal bodies. Moreover, GMNC and MCI associate differentially with the cell-cycle regulators E2F4 and E2F5, which enables them to activate distinct sets of target genes (ciliary transcription factor genes versus basal body amplification genes). Our data establish a previously unrecognized two-step model for MCC development: GMNC functions in the initial step for MCC precursor specification. GMNC induces Mci expression that drives the second step of basal body production for multiciliation.


Subject(s)
Cell Cycle Proteins/physiology , Cilia/physiology , Mice, Mutant Strains , Nuclear Proteins/physiology , Animals , Basal Bodies/physiology , Carrier Proteins/physiology , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , Cell Differentiation , Cell Nucleus/physiology , Ciliopathies , Gene Expression Regulation, Developmental , HEK293 Cells , Humans , Mice , Mice, Inbred C57BL , Mice, Knockout , Nuclear Proteins/genetics , Protein Domains , Zebrafish
7.
Nat Genet ; 50(12): 1666-1673, 2018 12.
Article in English | MEDLINE | ID: mdl-30420648

ABSTRACT

Straightening of the body axis is a major morphogenetic event that produces the typical head-to-tail shape of the vertebrate embryo. Defects in axial straightening can lead to debilitating disorders such as idiopathic scoliosis, characterized by three-dimensional curvatures of the spine1. Although abnormal cerebrospinal fluid (CSF) flow has been implicated in the development of idiopathic scoliosis2, the molecular mechanisms operating downstream of CSF flow remain obscure. Here we show that, in zebrafish embryos, cilia-driven CSF flow transports adrenergic signals that induce urotensin neuropeptides in CSF-contacting neurons along the spinal cord. Urotensins activate their receptor on slow-twitch muscle fibers of the dorsal somite; the contraction of these fibers likely results in straightening of the body axis. Consistent with this, mutation of the urotensin receptor resulted in severe scoliosis in adult zebrafish, closely mimicking the human disorder. These findings suggest that disruption of urotensin signaling by impaired CSF flow could be a critical etiological factor underlying the pathology of idiopathic scoliosis.


Subject(s)
Cerebrospinal Fluid/physiology , Cilia/physiology , Urotensins/genetics , Animals , Animals, Genetically Modified , Body Patterning , Embryo, Nonmammalian , Gene Expression Regulation, Developmental , Morphogenesis/physiology , Neuropeptides/genetics , Signal Transduction/genetics , Spinal Cord/embryology , Vertebrates/embryology , Zebrafish/embryology , Zebrafish/genetics
8.
Dev Biol ; 443(2): 165-172, 2018 11 15.
Article in English | MEDLINE | ID: mdl-30218642

ABSTRACT

Multiciliated cells (MCCs) differentiate arrays of motile cilia that beat to drive fluid flow over epithelia. Recent studies have established two Geminin family coiled-coil containing nuclear regulatory proteins, Gmnc and Multicilin (Mci), in the specification and differentiation of the MCCs. Both Gmnc and Mci are devoid of a DNA binding domain: they regulate transcription by associating with E2f family transcription factors, notably E2f4 and E2f5. Here, we have studied the relative contribution of these two E2f factors in MCC development using the zebrafish embryo, which differentiates MCCs within kidney tubules and the nose. We found that while E2f4 is fully dispensable, E2f5 is essential for MCCs to form in the kidney tubules. Moreover, using a variety of double mutant combinations we show that E2f5 has a more prominent role in MCC development in the zebrafish than E2f4. This contrasts with current evidence from the mouse, where E2f4 seems to be more important. Thus, distinct combinatorial activities of the E2f4 and E2f5 proteins regulate the specification and differentiation of MCCs in zebrafish and mice.


Subject(s)
E2F4 Transcription Factor/metabolism , E2F5 Transcription Factor/metabolism , Zebrafish/embryology , Animals , Cell Cycle Proteins/metabolism , Cell Differentiation/genetics , Cilia/metabolism , Cilia/physiology , E2F4 Transcription Factor/physiology , E2F5 Transcription Factor/physiology , Gene Expression Regulation, Developmental/genetics , HEK293 Cells , Humans , Nuclear Proteins/metabolism , Transcription Factors , Zebrafish/genetics , Zebrafish/metabolism , Zebrafish Proteins/genetics , Zebrafish Proteins/metabolism
10.
Curr Biol ; 25(24): 3267-73, 2015 Dec 21.
Article in English | MEDLINE | ID: mdl-26778655

ABSTRACT

Multiciliated cells (MCCs) differentiate hundreds of motile cilia that generate mechanical force required to drive fluid movement over epithelia [1, 2]. For example, metachronal beating of MCC cilia in the mammalian airways clears mucus that traps inhaled pathogens and pollutants. Consequently, abnormalities in MCC differentiation or ciliary motility have been linked to an expanding spectrum of human airway diseases [3­6]. The current view posits that MCC precursors are singled out by the inhibition of Notch signaling. MCC precursors then support an explosive production of basal bodies, which migrate to the apical surface, dock with the plasma membrane, and seed the growth of multiple motile cilia. At the center of this elaborate differentiation program resides the coiled-coil-containing protein Multicilin, which transcriptionally activates genes for basal body production and the gene for FoxJ1, the master regulator for basal body docking, cilia formation, and motility [7, 8]. Here, using genetic analysis in the zebrafish embryo, we discovered that Gmnc is a novel determinant of the MCC fate. Like Multicilin, Gmnc is a coiled-coil-containing protein of the Geminin family. We show that Gmnc functions downstream of Notch signaling, but upstream of Multicilin in the developmental pathway controlling MCC specification. Moreover, we find that loss of Gmnc in Xenopus embryos also causes loss of MCC differentiation and that overexpression of the protein is sufficient to induce supernumerary MCCs. Together, our data identify Gmnc as an evolutionarily conserved master regulator functioning at the top of the hierarchy of transcription factors involved in MCC differentiation.


Subject(s)
Carrier Proteins/physiology , Cell Differentiation , Mucous Membrane/embryology , Nuclear Proteins/physiology , Xenopus Proteins/physiology , Zebrafish Proteins/physiology , Animals , Basal Bodies/physiology , Cell Cycle Proteins , E2F Transcription Factors/metabolism , Embryo, Nonmammalian , Forkhead Transcription Factors/metabolism , Receptors, Notch/metabolism , Xenopus , Xenopus Proteins/metabolism , Zebrafish
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