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Constitutive activation of hedgehog signaling adversely affects epithelial cell fate during palatal fusion

Dev Biol.

2018 Jul 05

Li J, Yuan Y, He J, Feng J, Han X, Jing J, Ho TV, Xu J, Chai Y.
PMID: 29981310 | DOI: 10.1016/j.ydbio.2018.07.003

Cleft palate is one of the most common craniofacial congenital defects in humans. It is associated with multiple genetic and environmental risk factors, including mutations in the genes encoding signaling molecules in the sonic hedgehog (Shh) pathway, which are risk factors for cleft palate in both humans and mice. However, the function of Shh signaling in the palatal epithelium during palatal fusion remains largely unknown. Although components of the Shh pathway are localized in the palatal epithelium, specific inhibition of Shh signaling in palatal epithelium does not affect palatogenesis. We therefore utilized a hedgehog (Hh) signaling gain-of-function mouse model, K14-Cre;R26SmoM2, to uncover the role of Shh signaling in the palatal epithelium during palatal fusion. In this study, we discovered that constitutive activation of Hh signaling in the palatal epithelium results in submucous cleft palate and persistence of the medial edge epithelium (MEE). Further investigation revealed that precise downregulation of Shh signaling is required at a specific time point in the MEE during palatal fusion. Upregulation of Hh signaling in the palatal epithelium maintains the proliferation of MEE cells. This may be due to a dysfunctional p63/Irf6 regulatory loop. The resistance of MEE cells to apoptosis is likely conferred by enhancement of a cell adhesion network through the maintenance of p63 expression. Collectively, our data illustrate that persistent Hh signaling in the palatal epithelium contributes to the etiology and pathogenesis of submucous cleft palate through its interaction with a p63/Irf6-dependent biological regulatory loop and through a p63-induced cell adhesion network.

ADAMTS18 regulates early branching morphogenesis of lacrimal gland and has a significant association with the risk of dry eye in mice

Experimental eye research

2022 Feb 28

Wang, L;Sun, M;Zhang, Q;Dang, S;Zhang, W;
PMID: 35240198 | DOI: 10.1016/j.exer.2022.109020

ADAMTS18 is an orphan member of the ADAMTS family of metalloproteinase. ADAMTS18 mutation has been linked to developmental eye disorders, such as retinal dystrophies and ectopia lentis. Here, we report a new function of ADAMTS18 in modulating the lacrimal gland (LG) branching morphogenesis, and an association with dry eye in mice. Adamts18 mRNA was found to be enriched in the epithelium of branching tips of embryonic (E) LG, but its expression was barely detectable after 2 weeks of birth. Histological analyses of E16.5-E17.5 LG showed that ADAMTS18 deficiency resulted in a significant reduction of epithelial branching in embryonic LG. In vitro culture of E15.5 LG explants showed that the numbers of epithelial buds and branches in Adamts18 knockout (Adamts18-/-) LGs were significantly decreased when compared to those of wild type (Adamts18+/+) LGs after 0 h, 24 h, and 48 h of culture. Increased fibronectin deposition was detected in LG mesenchyme of E16.5 Adamts18-/- mice. At 14 months of age, Adamts18-/- mice manifested multiple LG pathological changes, including acinar atrophy and irregular duct ectasis with periductal fibrosis. The tear volume was significantly decreased in Adamts18-/- mice at 4 months of age, which corresponds to early adulthood in humans.
ADAMTS18 regulates vaginal opening through influencing the fusion of Mullerian duct and apoptosis of vaginal epithelial cells in mice

Reproductive biology

2021 Jul 13

Lin, X;Wang, C;Zhang, Q;Pan, YH;Dang, S;Zhang, W;
PMID: 34271244 | DOI: 10.1016/j.repbio.2021.100537

The ADAMTS (A Disintegrin and Metalloproteinase with Thrombospondin Motifs) enzymes are secreted metalloproteinases with major roles in development, morphogenesis, and tissue repair via the assembly and degradation of extracellular matrix (ECM). In this study, we investigated the role of ADAMTS18 in the development of the reproductive tract in female mice by phenotyping Adamts18 knockout (Adamts18-/-) mice. The results showed that Adamst18 mRNAs were abundantly expressed in vaginal epithelial cells and muscularis cells of the developing vagina. At the time of vaginal opening (5 weeks of age), about 41 % of Adamts18-/- females showed enlarged protrusions in the upper and middle parts of the vagina, reduced vaginal length, and simultaneously exhibited vaginal atresia. 6% Adamts18-/- females exhibited vaginal septum. Histological analyses revealed that the paired Mullerian ducts in ∼33 % female Adamts18-/- embryos failed to fuse at embryonic day 15.5 (E15.5) resulting in the formation of two vaginal cavities. Results of TUNEL assay and immunohistochemistry for caspase-3 showed that the number of apoptotic cells in the terminal portion of the vagina of 5-week-old Adamts18-/- females with vaginal atresia was significantly decreased. Adamts18-/- females also showed a significant decrease in serum estradiol E2 compared to age-matched Adamts18+/+ females. Results of qRT-PCR showed that the expression level of the anti-apoptosis gene Bcl-2 was significantly increased and that of the apoptosis-related gene Epha1 was decreased in the vagina of 5-week-old Adamts18-/- females. These results suggest that ADAMTS18 regulates vaginal opening through influencing the fusion of Mullerian ducts and apoptosis of vaginal cells in mice.
ADAMTS18 Deficiency Affects Neuronal Morphogenesis and Reduces the Levels of Depression-like Behaviors in Mice.

Neuroscience. 2018 Dec 21.

2018 Dec 21

Zhu R, Pan YH, Sun L, Zhang T, Wang C, Ye S, Yang N, Lu T, Wisniewski T, Dang S, Zhang W.
PMID: 30579834 | DOI: 10.1016/j.neuroscience.2018.12.025

The ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) enzymes are secreted, multi-domain matrix-associated zinc metalloendopeptidases that modify extracellular matrix components and play crucial roles in development and numerous diseases. ADAMTS18 is a member of the ADAMTS family, and genome-wide association studies made an initial association of ADAMTS18 with white matter integrity in healthy people of 72-74 years old. However, the potential roles of ADAMTS18 in central nervous system remain unclear. In this study, we showed that Adamts18 mRNA is highly abundant in developing brains, especially in the cerebellum granular cell layer and the hippocampus dentate gyrus (DG) granular cell layer. Adamts18 knockout (KO) mice displayed higher dendritic branching complexity and spine density on hippocampal DG granular cells. Behavioral tests showed that Adamts18 KO mice had reduced levels of depression-like behaviors compared to their wild-type (WT) littermates. The increased neurite formation could be attributed in part to reduced phosphorylation levels of the collapsin response mediator protein-2 (CRMP2) due to activation of the laminin/PI3K/AKT/GSK-3β signaling pathway. Our findings revealed a critical role of ADAMTS18 in neuronal morphogenesis and emotional control in mice.
Regulation and Role of GLI1 in Cutaneous Squamous Cell Carcinoma Pathogenesis.

Front Genet

2019 Dec 04

Pyczek J, Khizanishvili N, Kuzyakova M, Zabel S, Bauer J, Nitzki F, Emmert S, Sch�n MP, Boukamp P, Schildhaus HU, Uhmann A, Hahn H
PMID: 31867038 | DOI: 10.3389/fgene.2019.01185

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin tumor in humans. Although current therapies are sufficient to clear the tumor in many cases, the overall risk of cSCC metastasis is still 5%. Alternative treatment options could help to overcome this situation. Here we focused on the role of the Hedgehog (HH) signaling pathway and its interplay with epidermal growth factor receptor (EGFR) signaling in cSCC. The analyses revealed that, despite lack of Sonic HH (SHH) expression, a subset of human cSCC can express GLI1, a marker for active HH signaling, within distinct tumor areas. In contrast, all tumors strongly express EGFR and the hair follicle stem cell marker SOX9 at the highly proliferative tumor-stroma interface, whereas central tumor regions with a more differentiated stratum spinosum cell type lack both EGFR and SOX9 expression. In vitro experiments indicate that activation of EGFR signaling in the human cSCC cell lines SCL-1, MET-1, and MET-4 leads to GLI1 inhibition via the MEK/ERK axis without affecting cellular proliferation. Of note, EGFR activation also inhibits cellular migration of SCL-1 and MET-4 cells. Because proliferation and migration of the cells is also not altered by a GLI1 knockdown, GLI1 is apparently not involved in processes of aggressiveness in established cSCC tumors. In contrast, our data rather suggest a negative correlation between Gli1 expression level and cSCC formation because skin of Ptch +/- mice with slightly elevated Gli1 expression levels is significantly less susceptible to chemically-induced cSCC formation compared to murine wildtype skin. Although not yet formally validated, these data open the possibility that GLI1 (and thus HH signaling) may antagonize cSCC initiation and is not involved in cSCC aggressiveness, at least in a subset of cSCC.
Disruption of postnatal folliculogenesis and development of ovarian tumor in a mouse model with aberrant transforming growth factor beta signaling

Reprod Biol Endocrinol.

2017 Nov 08

Gao Y, Fang X, Vincent DF, Threadgill DW, Bartholin L, Li Q.
PMID: 29221447 | DOI: 10.1186/s12958-017-0312-z

Abstract

BACKGROUND:

Transforming growth factor beta (TGFB) superfamily signaling is implicated in the development of sex cord-stromal tumors, a category of poorly defined gonadal tumors. The aim of this study was to determine potential effects of dysregulated TGFB signaling in the ovary using Cre recombinase driven by growth differentiation factor 9 (Gdf9) promoter known to be expressed in oocytes.

METHODS:

A mouse model containing constitutively active TGFBR1 (TGFBR1CA) using Gdf9-iCre (termed TGFBR1-CAG9Cre) was generated. Hematoxylin and eosin (H & E) staining, follicle counting, and immunohistochemistry and immunofluorescence analyses using antibodies directed to Ki67, forkhead box L2 (FOXL2), forkhead box O1 (FOXO1), inhibin alpha (INHA), and SRY (sex determining region Y)-box 9 were performed to determine the characteristics of the TGFBR1-CAG9Cre ovary. Terminal deoxynucleotidyl transferase (TdT) labeling of 3'-OH ends of DNA fragments, real-time PCR, and western blotting were used to examine apoptosis, select gene expression, and TGFBR1 activation. RNAscope in situ hybridization was used to localize the expression of GLI-Kruppel family member GLI1 (Gli1) in ovarian tumortissues.

RESULTS:

TGFBR1-CAG9Cre females were sterile. Sustained activation of TGFBR1 led to altered granulosa cell proliferation evidenced by high expression of Ki67. At an early age, these mice demonstrated follicular defects and development of ovarian granulosa cell tumors, which were immunoreactive for granulosa cell markers including FOXL2, FOXO1, and INHA. Further histochemical and molecular analyses provided evidence of overactivation of TGFBR1 in the granulosa cell compartment during ovarian pathogenesis in TGFBR1-CAG9Cre mice, along with upregulation of Gli1 and Gli2 and downregulation of Tgfbr3 in ovarian tumor tissues.

CONCLUSIONS:

These results reinforce the role of constitutively active TGFBR1 in promoting ovarian tumorigenesis in mice. The mouse model created in this study may be further exploited to define the cellular and molecular mechanisms of TGFB/activin downstream signaling in granulosa cell tumor development. Future studies are needed to test whether activation of TGFB/activin signaling contributes to the development of human granulosa cell tumors.

Secreted metalloproteases ADAMTS9 and ADAMTS20 have a non-canonical role in ciliary vesicle growth during ciliogenesis.

Nat Commun.

2019 Feb 27

Nandadasa S, Kraft CM, Wang LW, O'Donnell A, Patel R, Gee HY, Grobe K, Cox TC, Hildebrandt F, Apte SS.
PMID: 30814516 | DOI: 10.1038/s41467-019-08520-7

Although hundreds of cytosolic or transmembrane molecules form the primary cilium, few secreted molecules are known to contribute to ciliogenesis. Here, homologous secreted metalloproteases ADAMTS9 and ADAMTS20 are identified as ciliogenesis regulators that act intracellularly. Secreted and furin-processed ADAMTS9 bound heparan sulfate and was internalized by LRP1, LRP2 and clathrin-mediated endocytosis to be gathered in Rab11 vesicles with a unique periciliary localization defined by super-resolution microscopy. CRISPR-Cas9 inactivation of ADAMTS9 impaired ciliogenesis in RPE-1 cells, which was restored by catalytically active ADAMTS9 or ADAMTS20 acting in trans, but not by their proteolytically inactive mutants. Their mutagenesis in mice impaired neural and yolk sac ciliogenesis, leading to morphogenetic anomalies resulting from impaired hedgehog signaling, which is transduced by primary cilia. In addition to their cognate extracellular proteolytic activity, ADAMTS9 and ADAMTS20 thus have an additional proteolytic role intracellularly, revealing an unexpected regulatory dimension in ciliogenesis.

Adamts18 modulates the development of aortic arch and common carotid artery

iScience

2021 May 01

Ye, S;Yang, N;Lu, T;Wu, T;Wang, L;Pan, Y;Cao, X;Yuan, X;Wisniewski, T;Dang, S;Zhang, W;
| DOI: 10.1016/j.isci.2021.102672

Members of the ADAMTS family have been implicated in various vascular diseases. However, their functional roles in early embryonic vascular development are unknown. In this study, we showed that Adamts18 is highly expressed at E11.5-E14.5 in cells surrounding the embryonic aortic arch (AOAR) and the common carotid artery (CCA) during branchial arch artery development in mice. Adamts18 deficiency was found to cause abnormal development of AOAR, CCA, and the 3rd and 4th branchial arch appendages, leading to hypoplastic carotid body, thymus, and variation of middle cerebral artery. Adamts18 was shown to affect the accumulation of extracellular matrix (ECM) components, in particular fibronectin (Fn), around AOAR and CCA. As a result of increased Fn accumulation, the Notch3 signaling pathway was activated to promote the differentiation of cranial neural crest cells (CNCCs) to vascular smooth muscle cells. These data indicate that Adamts18-mediated ECM homeostasis is crucial for the differentiation of CNCCs.
Steroidogenic differentiation and PKA signaling are programmed by histone methyltransferase EZH2 in the adrenal cortex.

Proc Natl Acad Sci U S A. 2018 Dec 12.

2018 Dec 12

Mathieu M, Drelon C, Rodriguez S, Tabbal H, Septier A, Damon-Soubeyrand C, Dumontet T, Berthon A, Sahut-Barnola I, Djari C, Batisse-Lignier M, Pointud JC, Richard D, Kerdivel G, Calméjane MA, Boeva V, Tauveron I, Lefrançois-Martinez AM, Martinez A, Val P.
PMID: 30541888 | DOI: 10.1073/pnas.1809185115

Adrenal cortex steroids are essential for body homeostasis, and adrenal insufficiency is a life-threatening condition. Adrenal endocrine activity is maintained through recruitment of subcapsular progenitor cells that follow a unidirectional differentiation path from zona glomerulosa to zona fasciculata (zF). Here, we show that this unidirectionality is ensured by the histone methyltransferase EZH2. Indeed, we demonstrate that EZH2 maintains adrenal steroidogenic cell differentiation by preventing expression of GATA4 and WT1 that cause abnormal dedifferentiation to a progenitor-like state in Ezh2 KO adrenals. EZH2 further ensures normal cortical differentiation by programming cells for optimal response to adrenocorticotrophic hormone (ACTH)/PKA signaling. This is achieved by repression of phosphodiesterases PDE1B, 3A, and 7A and of PRKAR1B. Consequently, EZH2 ablation results in blunted zF differentiation and primary glucocorticoid insufficiency. These data demonstrate an all-encompassing role for EZH2 in programming steroidogenic cells for optimal response to differentiation signals and in maintaining their differentiated state.
A cell identity switch allows residual BCC to survive Hedgehog pathway inhibition.

Nature.

2018 Oct 08

Biehs B, Dijkgraaf GJP, Piskol R, Alicke B, Boumahdi S, Peale F, Gould SE, de Sauvage FJ.
PMID: 30297801 | DOI: 10.1038/s41586-018-0596-y

Despite the efficacy of Hedgehog pathway inhibitors in the treatment of basal cell carcinoma (BCC)1, residual disease persists in some patients and may contribute to relapse when treatment is discontinued2. Here, to study the effect of the Smoothened inhibitor vismodegib on tumour clearance, we have used a Ptch1-Trp53 mouse model of BCC3 and found that mice treated with vismodegib harbour quiescent residual tumours that regrow upon cessation of treatment. Profiling experiments revealed that residual BCCs initiate a transcriptional program that closely resembles that of stem cells of the interfollicular epidermis and isthmus, whereas untreated BCCs are more similar to the hair follicle bulge. This cell identity switch was enabled by a mostly permissive chromatin state accompanied by rapid Wnt pathway activation and reprogramming of super enhancers to drive activation of key transcription factors involved in cellular identity. Accordingly, treatment of BCC with both vismodegib and a Wnt pathway inhibitor reduced the residual tumour burden and enhanced differentiation. Our study identifies a resistance mechanism in which tumour cells evade treatment by adopting an alternative identity that does not rely on the original oncogenic driver for survival.

Tumor Architecture and Notch Signaling Modulate Drug Response in Basal Cell Carcinoma

Cancer Cell

2018 Jan 27

Eberl M, Mangelberger D, Swanson JB, Verhaegen ME, Harms PW, Frohm ML, Dlugosz AA, Wong SY.
PMID: - | DOI: 10.1016/j.ccell.2017.12.015

Hedgehog (Hh) pathway inhibitors such as vismodegib are highly effective for treating basal cell carcinoma (BCC); however, residual tumor cells frequently persist and regenerate the primary tumor upon drug discontinuation. Here, we show that BCCs are organized into two molecularly and functionally distinct compartments. Whereas interior Hh+/Notch+ suprabasal cells undergo apoptosis in response to vismodegib, peripheral Hh+++/Notch− basal cells survive throughout treatment. Inhibiting Notch specifically promotes tumor persistence without causing drug resistance, while activating Notch is sufficient to regress already established lesions. Altogether, these findings suggest that the three-dimensional architecture of BCCs establishes a natural hierarchy of drug response in the tumor and that this hierarchy can be overcome, for better or worse, by modulating Notch.

Stem cell plasticity enables hair regeneration following Lgr5+ cell loss.

Nat Cell Biol.

2017 May 29

Hoeck JD, Biehs B, Kurtova AV, Kljavin NM, de Sousa E Melo F, Alicke B, Koeppen H, Modrusan Z, Piskol R, de Sauvage FJ.
PMID: 28553937 | DOI: 10.1038/ncb3535

Under injury conditions, dedicated stem cell populations govern tissue regeneration. However, the molecular mechanisms that induce stem cell regeneration and enable plasticity are poorly understood. Here, we investigate stem cell recovery in the context of the hair follicle to understand how two molecularly distinct stem cell populations are integrated. Utilizing diphtheria-toxin-mediated cell ablation of Lgr5+(leucine-rich repeat-containing G-protein-coupled receptor 5) stem cells, we show that killing of Lgr5+ cells in mice abrogates hair regeneration but this is reversible. During recovery, CD34+ (CD34 antigen) stem cells activate inflammatory response programs and start dividing. Pharmacological attenuation of inflammation inhibits CD34+ cell proliferation. Subsequently, the Wnt pathway controls the recovery of Lgr5+ cells and inhibition of Wnt signalling prevents Lgr5+ cell and hair germ recovery. Thus, our study uncovers a compensatory relationship between two stem cell populations and the underlying molecular mechanisms that enable hair follicle regeneration.

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Description
sense
Example: Hs-LAG3-sense
Standard probes for RNA detection are in antisense. Sense probe is reverse complent to the corresponding antisense probe.
Intron#
Example: Mm-Htt-intron2
Probe targets the indicated intron in the target gene, commonly used for pre-mRNA detection
Pool/Pan
Example: Hs-CD3-pool (Hs-CD3D, Hs-CD3E, Hs-CD3G)
A mixture of multiple probe sets targeting multiple genes or transcripts
No-XSp
Example: Hs-PDGFB-No-XMm
Does not cross detect with the species (Sp)
XSp
Example: Rn-Pde9a-XMm
designed to cross detect with the species (Sp)
O#
Example: Mm-Islr-O1
Alternative design targeting different regions of the same transcript or isoforms
CDS
Example: Hs-SLC31A-CDS
Probe targets the protein-coding sequence only
EnEmProbe targets exons n and m
En-EmProbe targets region from exon n to exon m
Retired Nomenclature
tvn
Example: Hs-LEPR-tv1
Designed to target transcript variant n
ORF
Example: Hs-ACVRL1-ORF
Probe targets open reading frame
UTR
Example: Hs-HTT-UTR-C3
Probe targets the untranslated region (non-protein-coding region) only
5UTR
Example: Hs-GNRHR-5UTR
Probe targets the 5' untranslated region only
3UTR
Example: Rn-Npy1r-3UTR
Probe targets the 3' untranslated region only
Pan
Example: Pool
A mixture of multiple probe sets targeting multiple genes or transcripts

Enabling research, drug development (CDx) and diagnostics

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