Publications by authors named "Adam Diehl"

16 Publications

  • Page 1 of 1

HEYL Regulates Neoangiogenesis Through Overexpression in Both Breast Tumor Epithelium and Endothelium.

Front Oncol 2020 15;10:581459. Epub 2021 Jan 15.

Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, United States.

Blocking tumor angiogenesis is an appealing therapeutic strategy, but to date, success has been elusive. We previously identified HEYL, a downstream target of Notch signaling, as an overexpressed gene in both breast cancer cells and as a tumor endothelial marker, suggesting that HEYL overexpression in both compartments may contribute to neoangiogenesis. Carcinomas arising in double transgenic Her2-neu/HeyL mice showed higher tumor vessel density and significantly faster growth than tumors in parental Her2/neu mice. Providing mechanistic insight, microarray-based mRNA profiling of HS578T-tet-off-HEYL human breast cancer cells revealed upregulation of several angiogenic factors including CXCL1/2/3 upon HEYL expression, which was validated by RT-qPCR and protein array analysis. Upregulation of the cytokines CXCL1/2/3 occurred through direct binding of HEYL to their promoter sequences. We found that vessel growth and migration of human vascular endothelial cells (HUVECs) was promoted by conditioned medium from HS578T-tet-off-HEYL carcinoma cells, but was blocked by neutralizing antibodies against CXCL1/2/3. Supporting these findings, suppressing HEYL expression using shRNA in MDA-MB-231 cells significantly reduced tumor growth. In addition, suppressing the action of proangiogenic cytokines induced by HEYL using a small molecule inhibitor of the CXCl1/2/3 receptor, CXCR2, in combination with the anti-VEGF monoclonal antibody, bevacizumab, significantly reduced tumor growth of MDA-MB-231 xenografts. Thus, HEYL expression in tumor epithelium has a profound effect on the vascular microenvironment in promoting neoangiogenesis. Furthermore, we show that lack of HEYL expression in endothelial cells leads to defects in neoangiogenesis, both under normal physiological conditions and in cancer. Thus, HeyL-/- mice showed impaired vessel outgrowth in the neonatal retina, while the growth of mammary tumor cells E0771 was retarded in syngeneic HeyL-/- mice compared to wild type C57/Bl6 mice. Blocking HEYL's angiogenesis-promoting function in both tumor cells and tumor-associated endothelium may enhance efficacy of therapy targeting the tumor vasculature in breast cancer.
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http://dx.doi.org/10.3389/fonc.2020.581459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7845423PMC
January 2021

MapGL: inferring evolutionary gain and loss of short genomic sequence features by phylogenetic maximum parsimony.

BMC Bioinformatics 2020 Sep 22;21(1):416. Epub 2020 Sep 22.

Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.

Background: Comparative genomics studies are growing in number partly because of their unique ability to provide insight into shared and divergent biology between species. Of particular interest is the use of phylogenetic methods to infer the evolutionary history of cis-regulatory sequence features, which contribute strongly to phenotypic divergence and are frequently gained and lost in eutherian genomes. Understanding the mechanisms by which cis-regulatory element turnover generate emergent phenotypes is crucial to our understanding of adaptive evolution. Ancestral reconstruction methods can place species-specific cis-regulatory features in their evolutionary context, thus increasing our understanding of the process of regulatory sequence turnover. However, applying these methods to gain and loss of cis-regulatory features historically required complex workflows, preventing widespread adoption by the broad scientific community.

Results: MapGL simplifies phylogenetic inference of the evolutionary history of short genomic sequence features by combining the necessary steps into a single piece of software with a simple set of inputs and outputs. We show that MapGL can reliably disambiguate the mechanisms underlying differential regulatory sequence content across a broad range of phylogenetic topologies and evolutionary distances. Thus, MapGL provides the necessary context to evaluate how genomic sequence gain and loss contribute to species-specific divergence.

Conclusions: MapGL makes phylogenetic inference of species-specific sequence gain and loss easy for both expert and non-expert users, making it a powerful tool for gaining novel insights into genome evolution.
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http://dx.doi.org/10.1186/s12859-020-03742-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7510305PMC
September 2020

Management of primary hepatic malignancies during the COVID-19 pandemic: recommendations for risk mitigation from a multidisciplinary perspective.

Lancet Gastroenterol Hepatol 2020 08 6;5(8):765-775. Epub 2020 Jun 6.

UCL Cancer Institute, University College London, London, UK; Department of Medical Physics and Biomedical Engineering, University College London, London, UK.

Around the world, recommendations for cancer treatment are being adapted in real time in response to the pandemic of COVID-19. We, as a multidisciplinary team, reviewed the standard management options, according to the Barcelona Clinic Liver Cancer classification system, for hepatocellular carcinoma. We propose treatment recommendations related to COVID-19 for the different stages of hepatocellular carcinoma (ie, 0, A, B, and C), specifically in relation to surgery, locoregional therapies, and systemic therapy. We suggest potential strategies to modify risk during the pandemic and aid multidisciplinary treatment decision making. We also review the multidisciplinary management of intrahepatic cholangiocarcinoma as a potentially curable and incurable diagnosis in the setting of COVID-19.
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http://dx.doi.org/10.1016/S2468-1253(20)30182-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274990PMC
August 2020

Transposable elements contribute to cell and species-specific chromatin looping and gene regulation in mammalian genomes.

Nat Commun 2020 04 14;11(1):1796. Epub 2020 Apr 14.

Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.

Chromatin looping is important for gene regulation, and studies of 3D chromatin structure across species and cell types have improved our understanding of the principles governing chromatin looping. However, 3D genome evolution and its relationship with natural selection remains largely unexplored. In mammals, the CTCF protein defines the boundaries of most chromatin loops, and variations in CTCF occupancy are associated with looping divergence. While many CTCF binding sites fall within transposable elements (TEs), their contribution to 3D chromatin structural evolution is unknown. Here we report the relative contributions of TE-driven CTCF binding site expansions to conserved and divergent chromatin looping in human and mouse. We demonstrate that TE-derived CTCF binding divergence may explain a large fraction of variable loops. These variable loops contribute significantly to corresponding gene expression variability across cells and species, possibly by refining sub-TAD-scale loop contacts responsible for cell-type-specific enhancer-promoter interactions.
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http://dx.doi.org/10.1038/s41467-020-15520-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156512PMC
April 2020

CGIMP: Real-time exploration and covariate projection for self-organizing map datasets.

J Open Source Softw 2019 10;4(39). Epub 2019 Jul 10.

Department of Computational Medicine and Bioinformatics, University of Michigan.

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http://dx.doi.org/10.21105/joss.01520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272009PMC
July 2019

Relationships between lymphocyte counts and treatment-related toxicities and clinical responses in patients with solid tumors treated with PD-1 checkpoint inhibitors.

Oncotarget 2017 Dec 14;8(69):114268-114280. Epub 2017 Dec 14.

The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.

The relationships between absolute lymphocyte counts (ALC), drug- related toxicities, and clinical responses remain unclear in cancer patients treated with PD-1 (programmed cell death 1) inhibitors. We performed a retrospective review of 167 adult solid tumor patients treated with nivolumab or pembrolizumab at a single institution between January 2015 and November 2016. Patients with an ALC >2000 at baseline had an increased risk of irAE (OR 1.996, p<0.05) on multivariate analysis. In a multivariate proportional hazards model, a shorter time to progression was noted in patients who were lymphopenic at baseline (HR 1.45 (p<0.05)) and at three months (HR 2.01 (p<0.05)). Patients with baseline lymphopenia and persistent lymphopenia at month 3 had a shorter time to progression compared to those who had baseline lymphopenia but recovered with ALC > 1000 at 3 months (HR 2.76, p<0.05). Prior radiation therapy was the characteristic most strongly associated with lymphopenia at 3 months (OR 2.24, p<0.001). These data suggest that patients with higher baseline lymphocyte counts have a greater risk for irAE, whereas patients with lymphopenia at baseline and persistent lymphopenia while on therapy have a shorter time to progression on these agents. These associations require further validation in additional patient cohorts.
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http://dx.doi.org/10.18632/oncotarget.23217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768402PMC
December 2017

Conserved and species-specific transcription factor co-binding patterns drive divergent gene regulation in human and mouse.

Nucleic Acids Res 2018 02;46(4):1878-1894

Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA.

The mouse is widely used as system to study human genetic mechanisms. However, extensive rewiring of transcriptional regulatory networks often confounds translation of findings between human and mouse. Site-specific gain and loss of individual transcription factor binding sites (TFBS) has caused functional divergence of orthologous regulatory loci, and so we must look beyond this positional conservation to understand common themes of regulatory control. Fortunately, transcription factor co-binding patterns shared across species often perform conserved regulatory functions. These can be compared to 'regulatory sentences' that retain the same meanings regardless of sequence and species context. By analyzing TFBS co-occupancy patterns observed in four human and mouse cell types, we learned a regulatory grammar: the rules by which TFBS are combined into meaningful regulatory sentences. Different parts of this grammar associate with specific sets of functional annotations regardless of sequence conservation and predict functional signatures more accurately than positional conservation. We further show that both species-specific and conserved portions of this grammar are involved in gene expression divergence and human disease risk. These findings expand our understanding of transcriptional regulatory mechanisms, suggesting that phenotypic divergence and disease risk are driven by a complex interplay between deeply conserved and species-specific transcriptional regulatory pathways.
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http://dx.doi.org/10.1093/nar/gky018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5829737PMC
February 2018

Evaluating the Accuracy of Sampling Strategies for Estimation of Compliance Rate for Ventilator-Associated Pneumonia Process Measures.

Infect Control Hosp Epidemiol 2016 09 20;37(9):1037-43. Epub 2016 Jun 20.

6Department of Population Medicine,Harvard Medical School & Harvard Pilgrim Health Care Institute,Boston,Massachusetts.

BACKGROUND Measuring processes of care performance rates is an invaluable tool for quality improvement; however, collecting daily process measure data is time-consuming and burdensome. OBJECTIVE To evaluate the accuracy of sampling strategies to estimate monthly compliance rates with ventilator-associated pneumonia prevention measures. SETTING AND PARTICIPANTS A total of 37 intensive care units affiliated with 29 hospitals participating in a 2-state 35-month ventilator-associated pneumonia prevention collaborative. Analysis was limited to 325 unit-months with complete data entry rates. METHODS We calculated unit-month level actual and sample monthly compliance rates for 6 ventilator-associated pneumonia prevention measures, using 4 sampling strategies: sample 1 day per month, sample 1 day per week, sample 7 consecutive days per month, and sample 7 consecutive days per month plus additional consecutive days as necessary to obtain at least 30 ventilator-days for that month whenever possible. We compared sample versus actual rates using paired t test and χ2 test. RESULTS Mean sampling accuracy ranged 84%-97% for 1 day per month, 91%-98% for 1 day per week, 92%-98% for 7 consecutive days per month, and 96%-99% for 7 consecutive days with at least 30 days per month if possible. The most accurate sampling strategy was to sample 7 consecutive days with at least 30 ventilator-days per month if possible. With this strategy, sample rates were within 10% of actual rates in 88%-99% of unit-months and within 5% of actual rates in 74%-97% of unit-months. CONCLUSION Sampling process measures intermittently rather than continually can yield accurate estimates of process measure performance rates. Infect Control Hosp Epidemiol 2016;37:1037-1043.
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http://dx.doi.org/10.1017/ice.2016.136DOI Listing
September 2016

Deciphering ENCODE.

Trends Genet 2016 Apr 5;32(4):238-249. Epub 2016 Mar 5.

Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA; Department of Human Genetics, University of Michigan, Ann Arbor MI 48109, USA. Electronic address:

The ENCODE project represents a major leap from merely describing and comparing genomic sequences to surveying them for direct indicators of function. The astounding quantity of data produced by the ENCODE consortium can serve as a map to locate specific landmarks, guide hypothesis generation, and lead us to principles and mechanisms underlying genome biology. Despite its broad appeal, the size and complexity of the repository can be intimidating to prospective users. We present here some background about the ENCODE data, survey the resources available for accessing them, and describe a few simple principles to help prospective users choose the data type(s) that best suit their needs, where to get them, and how to use them to their best advantage.
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http://dx.doi.org/10.1016/j.tig.2016.02.002DOI Listing
April 2016

An atypical 0.73 MB microduplication of 22q11.21 and a novel SALL4 missense mutation associated with thumb agenesis and radioulnar synostosis.

Am J Med Genet A 2015 Jul 30;167(7):1644-9. Epub 2015 Mar 30.

Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.

We describe a 0.73 Mb duplication of chromosome 22q11.21 between LCR-B and LCR-D and a missense mutation in a conserved C2H2 zinc finger domain of SALL4 in a cognitively normal patient with multiple skeletal anomalies including radioulnar synostosis, thumb aplasia, butterfly vertebrae, rib abnormalities, and hypoplasia of the humeral and femoral epiphyses. 22q11.21 is a common site for microdeletions and their reciprocal microduplications as a result of non-allelic homologous recombination between its multiple low copy repeat regions (LCR). DiGeorge /Velocardiofacial syndrome (DG/VCFS) is classically caused by a 3 Mb deletion between LCR-A and LCR-D or a 1.5 Mb deletion between LCR-A and LCR-B. The reciprocal syndrome to DG/VCFS is the recently described 22q11.2 microduplication, which usually presents with the typical 3 Mb or 1.5 Mb duplication. Numerous atypical deletions and duplications have been reported between other LCRs. Typically, SALL4-related Duane-radial ray syndrome is caused by deletions or nonsense mutations; the only missense SALL4 mutation described prior was thought to result in gain of function and produced cranial midline defects. The skeletal anomalies presented in this report have not been previously described in association with 22q11.2 microduplication nor SALL4 mutations.
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http://dx.doi.org/10.1002/ajmg.a.37066DOI Listing
July 2015

The Notch pathway inhibits TGFβ signaling in breast cancer through HEYL-mediated crosstalk.

Cancer Res 2014 Nov 12;74(22):6509-18. Epub 2014 Sep 12.

Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Acquired resistance to TGFβ is a key step in the early stages of tumorigenesis. Mutations in TGFβ signaling components are rare, and little is known about the development of resistance in breast cancer. On the other hand, an activated Notch pathway is known to play a substantial role in promoting breast cancer development. Here, we present evidence of crosstalk between these two pathways through HEYL. HEYL, a basic helix-loop-helix transcription factor and a direct target of Notch signaling, is specifically overexpressed in breast cancer. HEYL represses TGFβ activity by binding to TGFβ-activated Smads. HeyL(-/-) mice have defective mammary gland development with fewer terminal end buds. On the other hand, HeyL transgenic mice show accelerated mammary gland epithelial proliferation and 24% of multiparous mice develop mammary gland cancer. Therefore, repression of TGFβ signaling by Notch acting through HEYL may promote initiation of breast cancer.
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http://dx.doi.org/10.1158/0008-5472.CAN-14-0816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4233182PMC
November 2014

Horizontal integration of OMIM across the medical school preclinical curriculum for early reinforcement of clinical genetics principles.

Genet Med 2015 Feb 17;17(2):158-63. Epub 2014 Jul 17.

McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Purpose: With the relentless expansion of genetics into every field of medicine, stronger preclinical and clinical medical student education in genetics is needed. The explosion of genetic information cannot be addressed by simply adding content hours. We proposed that students be provided a tool to access accurate clinical information on genetic conditions and, through this tool, build life-long learning habits to carry them through their medical careers.

Methods: Surveys conducted at the Johns Hopkins University School of Medicine revealed that medical students in all years lacked confidence when approaching genetic conditions and lacked a reliable resource for accurate genetic information. In response, the school created a horizontal thread that stretches across the first-year curriculum and is devoted to teaching students how to use Online Mendelian Inheritance in Man (OMIM) (http://omim.org) and the databases to which it links as a starting point for approaching genetic conditions.

Results: The thread improved the first-year students' confidence in clinical genetics concepts and encouraged use of OMIM as a primary source for genetic information. Most students showed confidence in OMIM as a learning tool and wanted to see the thread repeated in subsequent years.

Conclusion: Incorporating OMIM into the preclinical curriculum improved students' confidence in clinical genetics concepts.
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http://dx.doi.org/10.1038/gim.2014.84DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4859213PMC
February 2015

Multiple sequence-specific DNA-binding proteins mediate estrogen receptor signaling through a tethering pathway.

Mol Endocrinol 2011 Apr 17;25(4):564-74. Epub 2011 Feb 17.

Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York 14853, USA.

The indirect recruitment (tethering) of estrogen receptors (ERs) to DNA through other DNA-bound transcription factors (e.g. activator protein 1) is an important component of estrogen-signaling pathways, but our understanding of the mechanisms of ligand-dependent activation in this pathway is limited. Using proteomic, genomic, and gene-specific analyses, we demonstrate that a large repertoire of DNA-binding transcription factors contribute to estrogen signaling through the tethering pathway. In addition, we define a set of endogenous genes for which ERα tethering through activator protein 1 (e.g. c-Fos) and cAMP response element-binding protein family members mediates estrogen responsiveness. Finally, we show that functional interplay between c-Fos and cAMP response element-binding protein 1 contributes to estrogen-dependent regulation through the tethering pathway. Based on our results, we conclude that ERα recruitment in the tethering pathway is dependent on the ligand-induced formation of transcription factor complexes that involves interplay between the transcription factors from different protein families.
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http://dx.doi.org/10.1210/me.2010-0425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3063082PMC
April 2011

Sequencing and comparative analysis of a conserved syntenic segment in the Solanaceae.

Genetics 2008 Sep 24;180(1):391-408. Epub 2008 Aug 24.

Department of Plant Breeding and Genetics, Wuhan Botanical Garden, Chinese Academy of Sciences, Wuhan, Hubei 430074, People's Republic of China.

Comparative genomics is a powerful tool for gaining insight into genomic function and evolution. However, in plants, sequence data that would enable detailed comparisons of both coding and noncoding regions have been limited in availability. Here we report the generation and analysis of sequences for an unduplicated conserved syntenic segment (CSS) in the genomes of five members of the agriculturally important plant family Solanaceae. This CSS includes a 105-kb region of tomato chromosome 2 and orthologous regions of the potato, eggplant, pepper, and petunia genomes. With a total neutral divergence of 0.73-0.78 substitutions/site, these sequences are similar enough that most noncoding regions can be aligned, yet divergent enough to be informative about evolutionary dynamics and selective pressures. The CSS contains 17 distinct genes with generally conserved order and orientation, but with numerous small-scale differences between species. Our analysis indicates that the last common ancestor of these species lived approximately 27-36 million years ago, that more than one-third of short genomic segments (5-15 bp) are under selection, and that more than two-thirds of selected bases fall in noncoding regions. In addition, we identify genes under positive selection and analyze hundreds of conserved noncoding elements. This analysis provides a window into 30 million years of plant evolution in the absence of polyploidization.
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http://dx.doi.org/10.1534/genetics.108.087981DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2535690PMC
September 2008

Genomic analyses of transcription factor binding, histone acetylation, and gene expression reveal mechanistically distinct classes of estrogen-regulated promoters.

Mol Cell Biol 2007 Jul 21;27(14):5090-104. Epub 2007 May 21.

Department of Molecular Biology and Genetics, Cornell University, 465 Biotechnology Building, Ithaca, NY 14853, USA.

To explore the global mechanisms of estrogen-regulated transcription, we used chromatin immunoprecipitation coupled with DNA microarrays to determine the localization of RNA polymerase II (Pol II), estrogen receptor alpha (ERalpha), steroid receptor coactivator proteins (SRC), and acetylated histones H3/H4 (AcH) at estrogen-regulated promoters in MCF-7 cells with or without estradiol (E2) treatment. In addition, we correlated factor occupancy with gene expression and the presence of transcription factor binding elements. Using this integrative approach, we defined a set of 58 direct E2 target genes based on E2-regulated Pol II occupancy and classified their promoters based on factor binding, histone modification, and transcriptional output. Many of these direct E2 target genes exhibit interesting modes of regulation and biological activities, some of which may be relevant to the onset and proliferation of breast cancers. Our studies indicate that about one-third of these direct E2 target genes contain promoter-proximal ERalpha-binding sites, which is considerably more than previous estimates. Some of these genes represent possible novel targets for regulation through the ERalpha/AP-1 tethering pathway. Our studies have also revealed several previously uncharacterized global features of E2-regulated gene expression, including strong positive correlations between Pol II occupancy and AcH levels, as well as between the E2-dependent recruitment of ERalpha and SRC at the promoters of E2-stimulated genes. Furthermore, our studies have revealed new mechanistic insights into E2-regulated gene expression, including the absence of SRC binding at E2-repressed genes and the presence of constitutively bound, promoter-proximally paused Pol IIs at some E2-regulated promoters. These mechanistic insights are likely to be relevant for understanding gene regulation by a wide variety of nuclear receptors.
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http://dx.doi.org/10.1128/MCB.00083-07DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1951957PMC
July 2007

Extraocular muscle morphogenesis and gene expression are regulated by Pitx2 gene dose.

Invest Ophthalmol Vis Sci 2006 May;47(5):1785-93

Department of Ophthalmology and Visual Sciences, University of Michigan Medical School, Ann Arbor 48105, USA.

Purpose: PITX2 gene dose plays a central role in Axenfeld-Rieger syndrome. The purpose of this study was to test the hypothesis that the effects of Pitx2 gene dose on eye development can be molecularly dissected in available Pitx2 mutant mice.

Methods: A panel of mice with Pitx2 gene dose ranging from wild-type (+/+) to none (-/-) was generated. Eye morphogenesis was assessed in animals with each Pitx2 gene dose. We also compared global gene expression in eye primordia taken from e12.5 Pitx2+/+, Pitx2+/-, Pitx2-/- embryos using gene microarrays. The validity of microarray results was confirmed by qRT-PCR.

Results: Morphogenesis of all extraocular muscle bundles correlated highly with Pitx2 gene dose, but there were some differences in sensitivity among muscle groups. Superior and inferior oblique muscles were most sensitive and disappeared before the four rectus muscles. Expression of muscle-specific genes was globally sensitive to Pitx2 gene dose, including the muscle-specific transcription factor genes Myf5, Myog, Myod1, Smyd1, Msc, and Csrp3.

Conclusions: Pitx2 gene dose regulates both morphogenesis and gene expression in developing extraocular muscles. The expression of key muscle-specific transcription factor genes is regulated by Pitx2 gene dose, suggesting that sufficient levels of PITX2 protein are essential for early initiation of the myogenic regulatory cascade in extraocular muscles. These results document the first ocular tissue affected by Pitx2 gene dose in a model organism, where the underlying mechanisms can be analyzed, and provide a paradigm for future experiments designed to elucidate additional effects of Pitx2 gene dose during eye development.
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http://dx.doi.org/10.1167/iovs.05-1424DOI Listing
May 2006