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Cancers
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Inhibitor of Growth (ING) Genes
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Inhibitor of Growth (ING) Genes

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (30 September 2020) | Viewed by 23982

Special Issue Editor

Dr. Rémy Pedeux

E-Mail Website
Guest Editor
INSERM U1242 COSS laboratory, Universit é de Rennes-1, 35042 Rennes, France
Interests: INhibitor or Growth genes, tumor suppressor genes, dna damage, dna repair, therapies; lung cancer; cell death; apoptosis; senescence; cell cycle

Special Issue Information

Dear Colleagues,

ING1 (Growth Inhibitor 1) was identified more than 20 years ago as a tumor suppressor gene. In the years that followed, it was revealed that ING1 belonged to a family of highly conserved proteins, both structurally and functionally, from yeast to human. In humans, there are 5 ING genes. Reports have shown that loss of expression of ING proteins is common in many tumor types. KO mice for ING1 or ING2 spontaneously develop tumors. Functionally, ING proteins are all involved in acetylation or deacetylation complexes and in chromatin remodeling. ING proteins have a PHD (Plant HomeoDomain) motif that has a strong affinity for the histone brand H3K4me3. Consequently, ING proteins are responsible for the targeting of histone acetylase or histone deacetylase complex to specific chromatin sites. ING proteins are involved in important functions such as cell cycle control, apoptosis and cellular senescence. The regulation of their functions remains little known; however, sumoylation of ING proteins appears to play an important role.

In this special issue, we will publish original journals and research that provide new insights into the role of ING genes in cancer. This will go from the mechanisms responsible for their loss of expression in human tumors to their functions in suppressive tumor signaling pathways and how these functions are regulated. Finally, information on how they can be used as markers or therapeutically targeted will be welcome.

Dr. Rémy Pedeux
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

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Published Papers (6 papers)

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12 pages, 1916 KiB  
Review
ING Proteins: Tumour Suppressors or Oncoproteins
by Karine Jacquet and Olivier Binda
Cancers 2021, 13(9), 2110; https://doi.org/10.3390/cancers13092110 - 27 Apr 2021
Cited by 10 | Viewed by 2298
Abstract
The INhibitor of Growth family was defined in the mid-1990s by the identification of a tumour suppressor, ING1, and subsequent expansion of the family based essentially on sequence similarities. However, later work and more recent investigations demonstrate that at least a few ING [...] Read more.
The INhibitor of Growth family was defined in the mid-1990s by the identification of a tumour suppressor, ING1, and subsequent expansion of the family based essentially on sequence similarities. However, later work and more recent investigations demonstrate that at least a few ING proteins are actually required for normal proliferation of eukaryotic cells, from yeast to human. ING proteins are also part of a larger family of chromatin-associated factors marked by a plant homeodomain (PHD), which mediates interactions with methylated lysine residues. Herein, we discuss the role of ING proteins and their various roles in chromatin signalling in the context of cancer development and progression. Full article
(This article belongs to the Special Issue Inhibitor of Growth (ING) Genes)
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Figure 1

Figure 1
<p>INhibitor of Growth (ING) proteins’ structure and complexes. (<b>A</b>) Phylogenic tree, domains, and conservation of the ING family. MBD: metal-binding domain responsible for zinc binding unique to ING1b. The MBD contains two subdomains: a PIP domain (PCNA-interacting protein motif) and a PDB domain (partial bromodomain); CR1 and 2: conserved regions 1 and 2; Lzip: leucine zipper-like region; NLS: nuclear localisation sequence; PHD: plant homeodomain responsible for binding to H3K4<sup>me3</sup>; PB: polybasic region unique to ING1 and ING2. ING4 and ING5 are paralogs that may form homo- or heterodimers in the cell [<a href="#B17-cancers-13-02110" class="html-bibr">17</a>,<a href="#B18-cancers-13-02110" class="html-bibr">18</a>]. ING1b and ING2 are close due to the presence of the PB motif in C-terminus. (<b>B</b>) ING protein association and targets. ING proteins are part of multiprotein complexes. There is a variable complexity of these complexes: from the TIP60 complex, which has around 18 stable subunits, to JADE or BRPF complexes, which harbour 5 subunits. INGs are all associated with an enzymatic activity implicated in the regulation of chromatin acetylation, on one side associated with the MYST (MOZ, Ybf2/Sas3, Sas2, and Tip60) family of acetyltransferases (HBO1 (KAT7), MOZ (KAT6A), MORF (KAT6B), Tip60 (KAT5) for ING3/4/5) but on the other side associated with the deacetylases HDAC1 (RPD3L1) and HDAC2 from the class I family of enzymes for ING1/2. The other subunits play an important targeting role in the ING complexes like the scaffolding subunits JADE (double PHD), BRBF (PZP, BD and PWWP), or EPC1/2 (EPcNI). Subunits having targeting function through chromatin reader domains are mentioned.</p> Full article ">Figure 2
<p>ING functions. ING proteins are peculiar chromatin readers with a PHD domain. They target their respective complexes to specific regions of the genome, where the different ING-containing complexes are responsible for posttranslational modifications (PTMs) of histones, as well as nonhistone proteins. These PTMs are involved in the regulation of many pathways during transcription, replication, DNA damage, and cell cycle arrest processes.</p> Full article ">
19 pages, 1935 KiB  
Review
Focus-ING on DNA Integrity: Implication of ING Proteins in Cell Cycle Regulation and DNA Repair Modulation
by Jérôme Archambeau, Alice Blondel and Rémy Pedeux
Cancers 2020, 12(1), 58; https://doi.org/10.3390/cancers12010058 - 24 Dec 2019
Cited by 13 | Viewed by 5202
Abstract
The ING family of tumor suppressor genes is composed of five members (ING1-5) involved in cell cycle regulation, DNA damage response, apoptosis and senescence. All ING proteins belong to various HAT or HDAC complexes and participate in chromatin remodeling that is essential for [...] Read more.
The ING family of tumor suppressor genes is composed of five members (ING1-5) involved in cell cycle regulation, DNA damage response, apoptosis and senescence. All ING proteins belong to various HAT or HDAC complexes and participate in chromatin remodeling that is essential for genomic stability and signaling pathways. The gatekeeper functions of the INGs are well described by their role in the negative regulation of the cell cycle, notably by modulating the stability of p53 or the p300 HAT activity. However, the caretaker functions are described only for ING1, ING2 and ING3. This is due to their involvement in DNA repair such as ING1 that participates not only in NERs after UV-induced damage, but also in DSB repair in which ING2 and ING3 are required for accumulation of ATM, 53BP1 and BRCA1 near the lesion and for the subsequent repair. This review summarizes evidence of the critical roles of ING proteins in cell cycle regulation and DNA repair to maintain genomic stability. Full article
(This article belongs to the Special Issue Inhibitor of Growth (ING) Genes)
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Figure 1

Figure 1
<p>Linear representation of ING proteins sequence. The LZL motif (orange striped) that allows the interaction with other proteins is present on ING2, ING3, ING4 and ING5 but not ING1. The NCR domain (blue), specific to the ING family, is shared between all the INGs. The NLS domain (green) is responsible for the nuclear localization of the protein and the PHD motif (yellow) for the binding to methylated histones.</p> Full article ">Figure 2
<p>ING proteins participate in chromatin remodeling. Chromatin compaction is regulated by posttranslational modifications such as histone methylation (mostly recognized as a compacted chromatin hallmark), and histone acetylation (favoring chromatin relaxation). ING1, in complex with HDAC1/2, promotes acetylation of H3 and H4 histones. This acetylation is also due to ING1-induced p300 activity. ING2, which can bind either H3K4me3 or H3K9me3, promotes respectively HAT activity or HMT activity. Conversely, ING3, as a member of hNuA4 complex, promotes HAT activity, notably thanks to TIP60 whose HAT activity is ING3-dependent, but also participates in inhibiting HMT activity via HP1 chaperone protein. ING4 and ING5 (both in complex with HBO1) were described as HAT promoting factors. ING5 was also described to inhibit the HMT Suv39h1 and the subsequent histone methylation.</p> Full article ">Figure 3
<p>ING proteins regulate cell cycle in a p53-dependent and independent manner. Cell cycle is negatively regulated by INGs in various ways. UPPER PART: ING1 by interacting with p53 promotes its activation of p21. By inhibiting both deacetylase (hSir2) and degradation of p53, ING1 stabilizes p53. In addition, Sin3a can interact with p53 and stabilize it, then inhibiting MDM2-associated degradation of p53. ING2, ING4 and ING5 can induce negative cell cycle regulation through p300 activation leading to the acetylation of p53. In addition, ING2 in complex with mSin3A can directly activate p21 expression thus inhibiting cell cycle independently of p53. Finally, ING3 by inhibiting the PI3K/AKT activation, can decrease the expression of cyclin D1 resulting in cell cycle arrest. LOWER PART: in response to DNA damage or genotoxic stress, ING1 can facilitate lesion bypass and further replication by promoting Rad18 loading onto chromatin. In a more physiological way, ING2 interaction with PCNA promotes the progression of the replication fork onto chromatin. ING5 also helps this progression by interacting with the MCM helicases, then preventing replication fork collapsing or replicative stress.</p> Full article ">Figure 4
<p>ING proteins are involved in the DNA Damage Response. ING1 is involved in UV damage: activated after UV damage, Chk1 phosphorylates ING1 on Ser126 which will stabilize it. ING1 is then able to promote XPA recruitment and subsequent DNA repair by NER. ING2, which facilitates NER, is also required in DSB repair in which it participates in 53BP1 accumulation at DSB sites. ING3 participates in the DDR pathway by promoting ATM activation and the signaling pathway that finally leads to the accumulation of 53BP1 or BRCA1 then initiating repair by either NHEJ or HR respectively. ING5 was described as a TIP60 cofactor that promotes BRCA1 accumulation thanks to H4K16 acetylation.</p> Full article ">
17 pages, 1175 KiB  
Review
Biological Functions of the ING Proteins
by Arthur Dantas, Buthaina Al Shueili, Yang Yang, Arash Nabbi, Dieter Fink and Karl Riabowol
Cancers 2019, 11(11), 1817; https://doi.org/10.3390/cancers11111817 - 19 Nov 2019
Cited by 29 | Viewed by 4484
Abstract
The proteins belonging to the inhibitor of growth (ING) family of proteins serve as epigenetic readers of the H3K4Me3 histone mark of active gene transcription and target histone acetyltransferase (HAT) or histone deacetylase (HDAC) protein complexes, in order to alter local chromatin structure. [...] Read more.
The proteins belonging to the inhibitor of growth (ING) family of proteins serve as epigenetic readers of the H3K4Me3 histone mark of active gene transcription and target histone acetyltransferase (HAT) or histone deacetylase (HDAC) protein complexes, in order to alter local chromatin structure. These multidomain adaptor proteins interact with numerous other proteins to facilitate their localization and the regulation of numerous biochemical pathways that impinge upon biological functions. Knockout of some of the ING genes in murine models by various groups has verified their status as tumor suppressors, with ING1 knockout resulting in the formation of large clear-cell B-lymphomas and ING2 knockout increasing the frequency of ameloblastomas, among other phenotypic effects. ING4 knockout strongly affects innate immunity and angiogenesis, and INGs1, ING2, and ING4 have been reported to affect apoptosis in different cellular models. Although ING3 and ING5 knockouts have yet to be published, preliminary reports indicate that ING3 knockout results in embryonic lethality and that ING5 knockout may have postpartum effects on stem cell maintenance. In this review, we compile the known information on the domains of the INGs and the effects of altering ING protein expression, to better understand the functions of this adaptor protein family and its possible uses for targeted cancer therapy. Full article
(This article belongs to the Special Issue Inhibitor of Growth (ING) Genes)
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Figure 1

Figure 1
<p>Domains of ING protein isoforms. ING proteins are well conserved throughout evolution. The plant homeodomain (PHD) allows these proteins to bind to the H3K4me3 histone mark and is present in all INGs. The lamin interacting domain (LID) is important so they can interact with lamin A and, at least for ING1, maintain nuclear morphology. Located within the nuclear localization sequence (NLS) that promotes translocation of the ING proteins to the nucleus by binding the karyopherin proteins are small, basic nucleolar targeting sequences (NTS). These direct ING1 to the nucleoli under conditions of stress, which promotes apoptosis. The NLS can also bind the p53 tumor suppressor. Proliferating cell nuclear antigen protein (PCNA) has been shown to bind specifically to ING1b via the PCNA-interacting protein (PIP) motif, and this interaction is also important for promoting apoptosis in response DNA-damage-induced stress. The polybasic region (PBR) is present only in ING1 and ING2. This motif can interact with both bioactive signaling phospholipids (PIs) and ubiquitin (Ub), the latter of which might serve to stabilize multi-monoubiquitination p53. The function of the partial bromodomain (PBD) has not been defined, but like the leucine zipper-like (LZL) region, may promote ING protein multimerization and/or interaction with other members of the HAT and HDAC complexes that ING proteins target to the H3K4Me3 histone mark.</p> Full article ">Figure 2
<p>Schematic figure showing the major phenotypes involved in the knockout animals for all the Ing proteins. Even though Ing proteins are relatively similar, their knockout phenotypes varied widely according to the protein deleted. ING1 knockout mice presented with reduced body sized, enlarged spleens and multiple B cells lymphomas. ING2 defective animals had deficient spermatogenesis. ING3 is the only Ing protein that was embryonically lethal, possibly because it is the most primordial of the family. ING4 mice were hypersensitive to LPS injection and presented problems with innate immunity. Lastly, there are still no knockouts for ING5, but based on the recent studies made in vitro that implicate ING5 in different stem cells processes, we expect to encounter some type of stem cell defect in these animals, possibly presenting as early age stem cell depletion or organogenesis defects.</p> Full article ">
14 pages, 1234 KiB  
Review
Exploiting ING2 Epigenetic Modulation as a Therapeutic Opportunity for Non-Small Cell Lung Cancer
by Alice Blondel, Amine Benberghout, Rémy Pedeux and Charles Ricordel
Cancers 2019, 11(10), 1601; https://doi.org/10.3390/cancers11101601 - 21 Oct 2019
Cited by 8 | Viewed by 4387
Abstract
Non-small cell lung cancer (NSCLC) has been the leading cause of cancer-related death worldwide, over the last few decades. Survival remains extremely poor in the metastatic setting and, consequently, innovative therapeutic strategies are urgently needed. Inhibitor of Growth Gene 2 (ING2) is a [...] Read more.
Non-small cell lung cancer (NSCLC) has been the leading cause of cancer-related death worldwide, over the last few decades. Survival remains extremely poor in the metastatic setting and, consequently, innovative therapeutic strategies are urgently needed. Inhibitor of Growth Gene 2 (ING2) is a core component of the mSin3A/Histone deacetylases complex (HDAC), which controls the chromatin acetylation status and modulates gene transcription. This gene has been characterized as a tumor suppressor gene and its status in cancer has been scarcely explored. In this review, we focused on ING2 and other mSin3A/HDAC member statuses in NSCLC. Taking advantage of existing public databases and known pharmacological properties of HDAC inhibitors, finally, we proposed a therapeutic model based on an ING2 biomarker-guided strategy. Full article
(This article belongs to the Special Issue Inhibitor of Growth (ING) Genes)
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Figure 1

Figure 1
<p>ING2 regulation of gene transcription through its interaction with H3K4me3 and the transcriptional regulator complex mSin3A/HDAC. (<b>A</b>) Protein structure of Human ING2. LZL—leucine zipper-like region; NCR—novel conserved region; NLS—nuclear localization signal, *within the NLS three short regions act as a nucleolar targeting signal (NTS); REASP—binding motif; PHD—plant homeodomain; PBR—polybasic region. ING2 structure was built according to UniProtKB ING2_Human (Q9H160). (<b>B</b>) Mammalian Sin3A/HDAC complex members. The core Sin3A subunits are depicted in green, the Sin3A associated proteins are depicted in blue, and the transcription factors are depicted in red. The names given for each complex member is the one approved by the HUGO Gene Nomenclature Committee (HGNC). (<b>C</b>) Schematic representation of ING2/H3K4me3/Sin3A formation regulating gene transcription. ING2 PHD domain recognizes trimethylated H3K4 (H3K4me3) as well as phosphatidylinositol 5-phosphate (PI(5)P) while the ING2 N-terminal part is detected by the transcriptional regulator complex mSin3-histone deacetylase. The ING2 sumoylation at Lysine 195 increases its association with this complex. An elevation in PI(5)P nuclear level triggers ING2/mSin3A complex relocalization to novel chromatin sites to regulate the transcription of target genes.</p> Full article ">Figure 2
<p>Despite <span class="html-italic">ING2</span> being rarely altered at the genomic level in cancers, genomic alteration of at least one member of the mSin3A/HDAC complex is frequent. (<b>A</b>) Bar graph showing the alteration frequency according to pathology (from the TCGA database). Blue represents gene deletion, red represents gene amplification, and green represents gene mutation. (<b>B</b>) Heatmap representing genomic alterations of mSin3A/HDAC members, according to NSCLC subtype (adenocarcinoma or squamous cell carcinoma) (from the TCGA database). First line is a pool of all mSin3A/HDAC member genomic alterations. Of note, specimens without any genomic alteration concerning the mSin3A/HDAC members are not depicted in the figure.</p> Full article ">Figure 3
<p>Co-dependency between <span class="html-italic">ING2</span> and mSin3A/HDAC complex members in tumor cell lines. (<b>A</b>) Graph depicting ranked Pearson correlation score between the CERES dependency score for each tested gene in the Cancer Dependency Map Project and the ING2 CERES dependency score. (<b>B</b>) Working model for a ING2 biomarker-based therapeutic strategy in NSCLC. Tumors expressing ING2 are more likely to depend on the oncogenic properties of mSin3A/HDAC for survival and could be targeted by suberoyl anilide hydroxamic acid (SAHA). Tumors that lose ING2 expression cannot be treated by SAHA, but can be treated by mSin3A direct inhibitors (mSin3Ai) or HDAC1/2 inhibitors (s.HDACi).</p> Full article ">
12 pages, 236 KiB  
Review
The Biological and Clinical Relevance of Inhibitor of Growth (ING) Genes in Non-Small Cell Lung Cancer
by Elisabeth Smolle, Nicole Fink-Neuboeck, Joerg Lindenmann, Freyja Smolle-Juettner and Martin Pichler
Cancers 2019, 11(8), 1118; https://doi.org/10.3390/cancers11081118 - 6 Aug 2019
Cited by 6 | Viewed by 2790
Abstract
Carcinogenic mutations allow cells to escape governing mechanisms that commonly inhibit uncontrolled cell proliferation and maintain tightly regulated homeostasis between cell death and survival. Members of the inhibition of growth (ING) family act as tumor suppressors, governing cell cycle, apoptosis and cellular senescence. [...] Read more.
Carcinogenic mutations allow cells to escape governing mechanisms that commonly inhibit uncontrolled cell proliferation and maintain tightly regulated homeostasis between cell death and survival. Members of the inhibition of growth (ING) family act as tumor suppressors, governing cell cycle, apoptosis and cellular senescence. The molecular mechanism of action of ING genes, as well as their anchor points in pathways commonly linked to malignant transformation of cells, have been studied with respect to a variety of cancer specimens. This review of the current literature focuses specifically on the action mode of ING family members in lung cancer. We have summarized data from in vitro and in vivo studies, highlighting the effects of varying levels of ING expression in cancer cells. Based on the increasing insight into the function of these proteins, the use of ING family members as clinically useful biomarkers for lung cancer detection and prognosis will probably become routine in everyday clinical practice. Full article
(This article belongs to the Special Issue Inhibitor of Growth (ING) Genes)

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13 pages, 1796 KiB  
Brief Report
Loss of Ing3 Expression Results in Growth Retardation and Embryonic Death
by Dieter Fink, Tienyin Yau, Arash Nabbi, Bettina Wagner, Christine Wagner, Shiting Misaki Hu, Viktor Lang, Stephan Handschuh, Karl Riabowol and Thomas Rülicke
Cancers 2020, 12(1), 80; https://doi.org/10.3390/cancers12010080 - 29 Dec 2019
Cited by 12 | Viewed by 4175
Abstract
The ING3 candidate tumour suppressor belongs to a family of histone modifying proteins involved in regulating cell proliferation, senescence, apoptosis, chromatin remodeling, and DNA repair. It is a stoichiometric member of the minimal NuA4 histone acetyl transferase (HAT) complex consisting of EAF6, EPC1, [...] Read more.
The ING3 candidate tumour suppressor belongs to a family of histone modifying proteins involved in regulating cell proliferation, senescence, apoptosis, chromatin remodeling, and DNA repair. It is a stoichiometric member of the minimal NuA4 histone acetyl transferase (HAT) complex consisting of EAF6, EPC1, ING3, and TIP60. This complex is responsible for the transcription of an essential cascade of genes involved in embryonic development and in tumour suppression. ING3 has been linked to head and neck and hepatocellular cancers, although its status as a tumour suppressor has not been well established. Recent studies suggest a pro-metastasis role in prostate cancer progression. Here, we describe a transgenic mouse strain with insertional mutation of an UbC-mCherry expression cassette into the endogenous Ing3 locus, resulting in the disruption of ING3 protein expression. Homozygous mutants are embryonically lethal, display growth retardation, and severe developmental disorders. At embryonic day (E) 10.5, the last time point viable homozygous embryos were found, they were approximately half the size of heterozygous mice that develop normally. µCT analysis revealed a developmental defect in neural tube closure, resulting in the failure of formation of closed primary brain vesicles in homozygous mid-gestation embryos. This is consistent with high ING3 expression levels in the embryonic brains of heterozygous and wild type mice and its lack in homozygous mutant embryos that show a lack of ectodermal differentiation. Our data provide direct evidence that ING3 is an essential factor for normal embryonic development and that it plays a fundamental role in prenatal brain formation. Full article
(This article belongs to the Special Issue Inhibitor of Growth (ING) Genes)
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Figure 1

Figure 1
<p>Quantification of overall fluorescence, schematic view of UbC-mCherry integration site, and embryo size. (<b>A</b>) Overall fluorescence of wild type (+/+; <span class="html-italic">n</span> = 4) and hemizygous (+/T; <span class="html-italic">n</span> = 8) UbC-mCherry mice, and hemizygous (+/T; <span class="html-italic">n</span> = 4) and homozygous (T/T; <span class="html-italic">n</span> = 4) CAG-mCherry mice. (<b>B</b>) Integration site of the UbC-mCherry cassette at 6qA3.1 disrupting the <span class="html-italic">Ing3</span> locus. (<b>C</b>) Embryo size of wild type (+/+; <span class="html-italic">n</span> = 9), heterozygous (+/T; <span class="html-italic">n</span> = 19), and homozygous (T/T; <span class="html-italic">n</span> = 8) <span class="html-italic">Ing3</span> insertional mutants at E10.5.</p> Full article ">Figure 2
<p>Protein expression in whole E10.5 embryos and the developing brain of E10.5 embryos. (<b>A</b>) Western blot analysis for ING3 of wild type (+/+; <span class="html-italic">n</span> = 1), heterozygous (+/T; <span class="html-italic">n</span> = 1), and homozygous (T/T; <span class="html-italic">n</span> = 2) whole embryos and intensity ratio readings ING3/Tubulin. (<b>B</b>) Immunohistochemisty for ING3 of wild type (+/+; <span class="html-italic">n</span> = 2), heterozygous (+/T; <span class="html-italic">n</span> = 2), and homozygous (T/T; <span class="html-italic">n</span> = 1) embryos. A representative section of the developing brain is shown and indicated by arrows. Magnification 40×.</p> Full article ">Figure 2 Cont.
<p>Protein expression in whole E10.5 embryos and the developing brain of E10.5 embryos. (<b>A</b>) Western blot analysis for ING3 of wild type (+/+; <span class="html-italic">n</span> = 1), heterozygous (+/T; <span class="html-italic">n</span> = 1), and homozygous (T/T; <span class="html-italic">n</span> = 2) whole embryos and intensity ratio readings ING3/Tubulin. (<b>B</b>) Immunohistochemisty for ING3 of wild type (+/+; <span class="html-italic">n</span> = 2), heterozygous (+/T; <span class="html-italic">n</span> = 2), and homozygous (T/T; <span class="html-italic">n</span> = 1) embryos. A representative section of the developing brain is shown and indicated by arrows. Magnification 40×.</p> Full article ">Figure 3
<p>µCT analysis of E10.5 embryos. Volume renderings show lateral view of (<b>A</b>) wild type (+/+; <span class="html-italic">n</span> = 4), (<b>B</b>) heterozygous (+/T; <span class="html-italic">n</span> = 4), and (<b>C</b>) homozygous (T/T; <span class="html-italic">n</span> = 3) embryos. Virtual µCT sections of (<b>D</b>,<b>E</b>,<b>F</b>,<b>G</b>) wild type, (<b>H</b>,<b>I</b>,<b>J</b>,<b>K</b>) heterozygous, and (<b>L</b>,<b>M</b>,<b>N</b>,<b>O</b>) homozygous embryos. Note that in (<b>A</b>) the tail bud was clipped unintentionally during specimen preparation and in (<b>B</b>) the hindlimb bud and tail bud are located behind the embryo head and thus are hidden in the image. (1, 2, 3: branchial bars 1–3; bb: brain bulges; ed: endolymphatic duct; fb: forelimb bud; hb: hindlimb bud; he: heart; lp: lens pit; me: mesencephalon; oc: optical cup; op: olfactory pit; os: optic stalk; ov: otic vesicle; rh: rhombencephalon; Rp: Rathke’s pouch; rs: retinal sheet; te: telencephalon).</p> Full article ">Figure 4
<p>Reconstitution of ING3 by ubiquitous expression of Ing3-P2A-eGFP. (<b>A</b>) Schematic view of the <span class="html-italic">Ing3</span> transposon construct. (<b>B</b>) In vivo imaging showing mCherry expression of different genotypes in a representative litter of a UbC-mCherry, CAG-Ing3-P2A-eGFP double mutant bred to a hemizygous UbC-mCherry mouse. (<b>C</b>) mCherry and eGFP expression with corresponding genotypes of UbC-mCherry and CAG-Ing3-P2A-eGFP transgenic pups (homozygous (T/T), hemizyous (+/T) and wild type (+/+)). Total numbers of animals per genotype are indicated in the figure. Position of genotyping primers are indicated by arrows.</p> Full article ">
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