Publications by authors named "Steven M Hrycaj"

15 Publications

  • Page 1 of 1

Gastrointestinal Pathology in Samples from Coronavirus Disease 2019 (COVID-19)-Positive Patients.

Arch Pathol Lab Med 2021 May 7. Epub 2021 May 7.

Department of Pathology, University of Michigan, Ann Arbor, MI.

Context: -Although primarily considered a respiratory illness, coronavirus disease 2019 (COVID-19) can cause gastrointestinal manifestations.

Objective: -To evaluate histopathology and in situ hybridization for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in gastrointestinal samples from patients with recent and remote COVID-19.

Design: -Patients with positive SARS-CoV-2 nasopharyngeal tests and a gastrointestinal tissue specimen were included. SARS-CoV-2 in situ hybridization (ISH) was performed on each sample. A subset had SARS-CoV-2 next generation sequencing (NGS) performed.

Results: -Twenty-five patients met inclusion criteria. Five had positive SARS-CoV-2 nasopharyngeal tests within 7 days of their gastrointestinal procedure. Two were ulcerative colitis patients on steroid therapy who lacked typical COVID-19 symptoms. Their colectomies showed severe ulcerative colitis; one demonstrated SARS-CoV-2 by NGS but a negative ISH. Another had an ischemic colon resected as a complication of the COVID-19 course; however, both ISH and NGS were negative. A fourth had a normal-appearing terminal ileum but positive ISH and NGS. The fifth patient had ileal ulcers with SARS-CoV-2 negativity by both modalities. The remaining 20 patients had positive nasopharyngeal tests an average of 53 days prior to procedure. None of their samples demonstrated SARS-CoV-2 ISH positivity, but one was positive on NGS despite a negative nasopharyngeal test.

Conclusions: -Gastrointestinal findings from SARS-CoV-2-infected patients ranged from normal with virus detected by ISH and NGS, to bowel ischemia secondary to systemic viral effects, without evidence of virus in the tissue. No distinct histologic finding was identified in those with gastrointestinal tissue specimens demonstrating SARS-CoV-2 positivity in this cohort.
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http://dx.doi.org/10.5858/arpa.2021-0137-SADOI Listing
May 2021

Immunohistochemical expression of PAX8, PAX2, and cytokeratin in melanomas.

J Cutan Pathol 2021 May 2. Epub 2021 May 2.

Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.

Background: Deviations from the classic melanocytic immunophenotype in melanoma can present a diagnostic challenge. PAX8 and PAX2 are common markers for renal or Müllerian differentiation. While most PAX8+ or PAX2+ carcinomas are seldom confused with melanoma, some cases may show a more ambiguous immunophenotype, especially when MiTF family altered renal cell carcinoma (MiTF-RCC) is in the differential diagnosis. Neither PAX8 nor PAX2 expression has been reported in melanoma to date. We aimed to better characterize PAX8, PAX2, and cytokeratin immunoreactivity in a large series of melanomas.

Methods: Tissue microarrays consisting of 263 melanomas were immunostained for PAX8, PAX2, and cytokeratin and graded by an h-score.

Results: PAX8 expression was seen in 7.9% of melanomas and was significantly associated with spindle cytomorphology. PAX2 was positive in one (0.4%) melanoma. Cytokeratin positivity was seen in three (1.2%) cases and was associated with metastases.

Conclusions: PAX8 is expressed in a subset of melanomas and may be strong/extensive. As PAX8 positivity does not exclude a diagnosis of melanoma, it should be used in conjunction with other immunohistochemical markers, such as cytokeratin and PAX2, when melanoma, MiTF-RCC, and other PAX8+ tumors are in the differential diagnosis.
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http://dx.doi.org/10.1111/cup.14041DOI Listing
May 2021

Stem cell transplantation uncovers TDO-AHR regulation of lung dendritic cells in herpesvirus-induced pathology.

JCI Insight 2021 01 25;6(2). Epub 2021 Jan 25.

Division of Pulmonary & Critical Care Medicine, Department of Internal Medicine, and.

The aryl-hydrocarbon receptor (AHR) is an intracellular sensor of aromatic hydrocarbons that sits at the top of various immunomodulatory pathways. Here, we present evidence that AHR plays a role in controlling IL-17 responses and the development of pulmonary fibrosis in response to respiratory pathogens following bone marrow transplant (BMT). Mice infected intranasally with gamma-herpesvirus 68 (γHV-68) following BMT displayed elevated levels of the AHR ligand, kynurenine (kyn), in comparison with control mice. Inhibition or genetic ablation of AHR signaling resulted in a significant decrease in IL-17 expression as well as a reduction in lung pathology. Lung CD103+ DCs expressed AHR following BMT, and treatment of induced CD103+ DCs with kyn resulted in altered cytokine production in response to γHV-68. Interestingly, mice deficient in the kyn-producing enzyme indolamine 2-3 dioxygenase showed no differences in cytokine responses to γHV-68 following BMT; however, isolated pulmonary fibroblasts infected with γHV-68 expressed the kyn-producing enzyme tryptophan dioxygenase (TDO2). Our data indicate that alterations in the production of AHR ligands in response to respiratory pathogens following BMT results in a pro-Th17 phenotype that drives lung pathology. We have further identified the TDO2/AHR axis as a potentially novel form of intercellular communication between fibroblasts and DCs that shapes immune responses to respiratory pathogens.
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http://dx.doi.org/10.1172/jci.insight.139965DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934859PMC
January 2021

genes direct elastin network formation during alveologenesis by regulating myofibroblast adhesion.

Proc Natl Acad Sci U S A 2018 11 22;115(45):E10605-E10614. Epub 2018 Oct 22.

Department of Internal Medicine, Division of Genetic Medicine, University of Michigan, Ann Arbor, MI 48109-2200;

genes (, , ) are exclusively expressed in the lung mesenchyme during embryogenesis, and the most severe phenotypes result from constitutive loss of function of all three genes. Because triple null mutants exhibit perinatal lethality, the contribution of this paralogous group to postembryonic lung development is unknown. Intriguingly, expression of all three genes peaks during the first 2 weeks after birth, reaching levels far exceeding those measured at embryonic stages, and surviving single and compound mutants exhibit defects in the localization of alveolar myofibroblasts. To define the contribution of the entire paralogous group to this process, we generated an conditional allele to use with our existing null alleles for and Postnatally, mesenchymal deletion of in an double-mutant background results in severe alveolar simplification. The elastin network required for alveolar formation is dramatically disrupted in triple mutants, while the basal lamina, interstitial matrix, and fibronectin are normal. Alveolar myofibroblasts remain Pdgfrα+/SMA+ double positive and present in normal numbers, indicating that the irregular elastin network is not due to fibroblast differentiation defects. Rather, we observe that SMA+ myofibroblasts of triple mutants are morphologically abnormal both in vivo and in vitro with highly reduced adherence to fibronectin. This loss of adhesion is a result of loss of the integrin heterodimer Itga5b1 in mutant fibroblasts. Collectively, these data show an important role for genes in lung fibroblast adhesion necessary for proper elastin network formation during alveologenesis.
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http://dx.doi.org/10.1073/pnas.1807067115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6233103PMC
November 2018

Loss of Hox5 function results in myofibroblast mislocalization and distal lung matrix defects during postnatal development.

Sci China Life Sci 2018 Sep 27;61(9):1030-1038. Epub 2018 Apr 27.

Department of Internal Medicine, Division of Molecular Medicine and Genetics, University of Michigan, Ann Arbor, MI, 48109-2200, USA.

Alveologenesis is the final stage of lung development and is responsible for the formation of the principle gas exchange units called alveoli. The lung mesenchyme, in particular the alveolar myofibroblasts, are drivers of alveolar development, however, few key regulators that govern the proper distribution and behavior of these cells in the distal lung during alveologenesis have been identified. While Hox5 triple mutants (Hox5 aabbcc) exhibit neonatal lethality, four-allele, compound mutant mice (Hox5 AabbCc) are born in Mendelian ratios and are phenotypically normal at birth. However, they exhibit defects in alveologenesis characterized by a BPD-like phenotype by early postnatal stages that becomes more pronounced at adult stages. Invasive pulmonary functional analyses demonstrate significant increases in total lung volume and compliance and a decrease in elastance in Hox5 compound mutants. SMA+ myofibroblasts in the distal lung are distributed abnormally during peak stages of alveologenesis and aggregate, resulting in the formation of a disrupted elastin network. Examination of other key components of the distal lung ECM, as well as other epithelial cells and lipofibroblasts reveal no differences in distribution. Collectively, these data indicate that Hox5 genes play a critical role in alveolar development by governing the proper cellular behavior of myofibroblasts during alveologenesis.
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http://dx.doi.org/10.1007/s11427-017-9290-1DOI Listing
September 2018

Paralogous Genes Modulate Th2 Cell Function during Chronic Allergic Inflammation via Regulation of .

J Immunol 2017 07 2;199(2):501-509. Epub 2017 Jun 2.

Department of Pathology, University of Michigan, Ann Arbor, MI 48109; and.

Allergic asthma is a significant health burden in western countries, and continues to increase in prevalence. Th2 cells contribute to the development of disease through release of the cytokines IL-4, IL-5, and IL-13, resulting in increased airway eosinophils and mucus hypersecretion. The molecular mechanisms behind the disease pathology remain largely unknown. In this study we investigated a potential regulatory role for the gene family, , , and , genes known to be important in lung development within mesenchymal cell populations. We found that -mutant mice show exacerbated pathology compared with wild-type controls in a chronic allergen model, with an increased Th2 response and exacerbated lung tissue pathology. Bone marrow chimera experiments indicated that the observed enhanced pathology was mediated by immune cell function independent of mesenchymal cell Hox5 family function. Examination of T cells grown in Th2 polarizing conditions showed increased proliferation, enhanced expression, and elevated production of IL-4, IL-5, and IL-13 in -deficient T cells compared with wild-type controls. Overexpression of FLAG-tagged HOX5 proteins in Jurkat cells demonstrated HOX5 binding to the locus and decreased and IL-4 expression, supporting a role for HOX5 proteins in direct transcriptional control of Th2 development. These results reveal a novel role for genes as developmental regulators of Th2 immune cell function that demonstrates a redeployment of mesenchyme-associated developmental genes.
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http://dx.doi.org/10.4049/jimmunol.1601826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5508748PMC
July 2017

Hox genes and evolution.

F1000Res 2016 10;5. Epub 2016 May 10.

Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, 48109-2200, USA; Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan, 48109-2200, USA.

Hox proteins are a deeply conserved group of transcription factors originally defined for their critical roles in governing segmental identity along the antero-posterior (AP) axis in Drosophila. Over the last 30 years, numerous data generated in evolutionarily diverse taxa have clearly shown that changes in the expression patterns of these genes are closely associated with the regionalization of the AP axis, suggesting that Hox genes have played a critical role in the evolution of novel body plans within Bilateria. Despite this deep functional conservation and the importance of these genes in AP patterning, key questions remain regarding many aspects of Hox biology. In this commentary, we highlight recent reports that have provided novel insight into the origins of the mammalian Hox cluster, the role of Hox genes in the generation of a limbless body plan, and a novel putative mechanism in which Hox genes may encode specificity along the AP axis. Although the data discussed here offer a fresh perspective, it is clear that there is still much to learn about Hox biology and the roles it has played in the evolution of the Bilaterian body plan.
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http://dx.doi.org/10.12688/f1000research.7663.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4863668PMC
May 2016

Mesenchymal Hox6 function is required for mouse pancreatic endocrine cell differentiation.

Development 2015 Nov 8;142(22):3859-68. Epub 2015 Oct 8.

Department of Internal Medicine, Division of Molecular Medicine and Genetics, University of Michigan, Ann Arbor, MI 48109-2200, USA Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, MI 48109-2200, USA Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109-2200, USA

Despite significant advances in our understanding of pancreatic endocrine cell development, the function of the pancreatic mesodermal niche in this process is poorly understood. Here we report a novel role for mouse Hox6 genes in pancreatic organogenesis. Hox6 genes are expressed exclusively in the mesoderm of the developing pancreas. Genetic loss of all three Hox6 paralogs (Hoxa6, Hoxb6 and Hoxc6) leads to a dramatic loss of endoderm-derived endocrine cells, including insulin-secreting β-cells, and to mild delays and disruptions in pancreatic branching and exocrine differentiation. Ngn3-expressing pan-endocrine progenitor cells are specified normally in Hox6 mutant pancreata, but fail to mature into hormone-producing cells. Reduced expression of Wnt5a is observed in mutant pancreatic mesenchyme, leading to subsequent loss of expression of the crucial Wnt inhibitors Sfrp3 and Dkk1 in endocrine progenitor cells. These results reveal a key role for Hox6 genes in establishing Wnt mesenchymal-epithelial crosstalk in pancreatic development.
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http://dx.doi.org/10.1242/dev.126888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4712882PMC
November 2015

Hox5 Genes Regulate the Wnt2/2b-Bmp4-Signaling Axis during Lung Development.

Cell Rep 2015 Aug 30;12(6):903-12. Epub 2015 Jul 30.

Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109-2200, USA; Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109-2200, USA. Electronic address:

Hox genes are required for proper anteroposterior axial patterning and the development of several organ systems. Here, we show that all three Hox5 paralogous genes play redundant roles in the developing lung. Hoxa5;Hoxb5;Hoxc5 triple-mutant embryos develop severely hypoplastic lungs with reduced branching and proximal-distal patterning defects. Hox5 genes are exclusively expressed in the lung mesoderm; however, defects are observed in both lung mesenchyme and endodermally derived epithelium, demonstrating that Hox5 genes act to regulate mesodermal-epithelial crosstalk during development. We show that Hox5 loss of function leads to loss of Wnt2/2b expression in the distal lung mesenchyme and the downregulation of previously identified downstream targets of Wnt2/2b signaling, including Lef1, Axin2, and Bmp4. Wnt2/2b-enriched media rescue proper Sox2/Sox9 patterning and restore Bmp4 expression in Hox5 triple-mutant lung explants. Taken together, these data show that Hox5 genes are key upstream mesenchymal regulators of the Wnt2/2b-Bmp4-signaling axis critical for proper lung patterning.
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http://dx.doi.org/10.1016/j.celrep.2015.07.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4536095PMC
August 2015

Wnt signaling inhibits adrenal steroidogenesis by cell-autonomous and non-cell-autonomous mechanisms.

Mol Endocrinol 2014 Sep 16;28(9):1471-86. Epub 2014 Jul 16.

Cellular and Molecular Biology Graduate Program (E.M.W., G.D.H.) and Program in Biomedical Sciences (N.B.), University of Michigan Medical School; Center for Cancer Biostatistics (R.K.), Department of Biostatistics, University of Michigan School of Public Health; Department of Internal Medicine (I.F., G.D.H.), Division of Metabolism, Endocrinology and Diabetes; Department of Internal Medicine (S.M.H., D.M.W.), Division of Molecular Medicine and Genetics; and Endocrine Oncology Program (G.D.H.), Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan 48109.

Wnt/β-catenin (βcat) signaling is critical for adrenal homeostasis. To elucidate how Wnt/βcat signaling elicits homeostatic maintenance of the adrenal cortex, we characterized the identity of the adrenocortical Wnt-responsive population. We find that Wnt-responsive cells consist of sonic hedgehog (Shh)-producing adrenocortical progenitors and differentiated, steroidogenic cells of the zona glomerulosa, but not the zona fasciculata and rarely cells that are actively proliferating. To determine potential direct inhibitory effects of βcat signaling on zona fasciculata-associated steroidogenesis, we used the mouse ATCL7 adrenocortical cell line that serves as a model system of glucocorticoid-producing fasciculata cells. Stimulation of βcat signaling caused decreased corticosterone release consistent with the observed reduced transcription of steroidogenic genes Cyp11a1, Cyp11b1, Star, and Mc2r. Decreased steroidogenic gene expression was correlated with diminished steroidogenic factor 1 (Sf1; Nr5a1) expression and occupancy on steroidogenic promoters. Additionally, βcat signaling suppressed the ability of Sf1 to transactivate steroidogenic promoters independent of changes in Sf1 expression level. To investigate Sf1-independent effects of βcat on steroidogenesis, we used Affymetrix gene expression profiling of Wnt-responsive cells in vivo and in vitro. One candidate gene identified, Ccdc80, encodes a secreted protein with unknown signaling mechanisms. We report that Ccdc80 is a novel βcat-regulated gene in adrenocortical cells. Treatment of adrenocortical cells with media containing secreted Ccdc80 partially phenocopies βcat-induced suppression of steroidogenesis, albeit through an Sf1-independent mechanism. This study reveals multiple mechanisms of βcat-mediated suppression of steroidogenesis and suggests that Wnt/βcat signaling may regulate adrenal homeostasis by inhibiting fasciculata differentiation and promoting the undifferentiated state of progenitor cells.
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http://dx.doi.org/10.1210/me.2014-1060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4154239PMC
September 2014

Hox5 interacts with Plzf to restrict Shh expression in the developing forelimb.

Proc Natl Acad Sci U S A 2013 Nov 11;110(48):19438-43. Epub 2013 Nov 11.

Department of Internal Medicine, Division of Molecular Medicine and Genetics, University of Michigan, Ann Arbor, MI 48109.

To date, only the five most posterior groups of Hox genes, Hox9-Hox13, have demonstrated loss-of-function roles in limb patterning. Individual paralog groups control proximodistal patterning of the limb skeletal elements. Hox9 genes also initiate the onset of Hand2 expression in the posterior forelimb compartment, and collectively, the posterior HoxA/D genes maintain posterior Sonic Hedgehog (Shh) expression. Here we show that an anterior Hox paralog group, Hox5, is required for forelimb anterior patterning. Deletion of all three Hox5 genes (Hoxa5, Hoxb5, and Hoxc5) leads to anterior forelimb defects resulting from derepression of Shh expression. The phenotype requires the loss of all three Hox5 genes, demonstrating the high level of redundancy in this Hox paralogous group. Further analyses reveal that Hox5 interacts with promyelocytic leukemia zinc finger biochemically and genetically to restrict Shh expression. These findings, along with previous reports showing that point mutations in the Shh limb enhancer lead to similar anterior limb defects, highlight the importance of Shh repression for proper patterning of the vertebrate limb.
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http://dx.doi.org/10.1073/pnas.1315075110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3845161PMC
November 2013

Sox9 plays multiple roles in the lung epithelium during branching morphogenesis.

Proc Natl Acad Sci U S A 2013 Nov 4;110(47):E4456-64. Epub 2013 Nov 4.

Department of Cell and Developmental Biology and Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109-2200.

Lung branching morphogenesis is a highly orchestrated process that gives rise to the complex network of gas-exchanging units in the adult lung. Intricate regulation of signaling pathways, transcription factors, and epithelial-mesenchymal cross-talk are critical to ensuring branching morphogenesis occurs properly. Here, we describe a role for the transcription factor Sox9 during lung branching morphogenesis. Sox9 is expressed at the distal tips of the branching epithelium in a highly dynamic manner as branching occurs and is down-regulated starting at embryonic day 16.5, concurrent with the onset of terminal differentiation of type 1 and type 2 alveolar cells. Using epithelial-specific genetic loss- and gain-of-function approaches, our results demonstrate that Sox9 controls multiple aspects of lung branching. Fine regulation of Sox9 levels is required to balance proliferation and differentiation of epithelial tip progenitor cells, and loss of Sox9 leads to direct and indirect cellular defects including extracellular matrix defects, cytoskeletal disorganization, and aberrant epithelial movement. Our evidence shows that unlike other endoderm-derived epithelial tissues, such as the intestine, Wnt/β-catenin signaling does not regulate Sox9 expression in the lung. We conclude that Sox9 collectively promotes proper branching morphogenesis by controlling the balance between proliferation and differentiation and regulating the extracellular matrix.
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http://dx.doi.org/10.1073/pnas.1311847110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3839746PMC
November 2013

Ezh2 orchestrates topographic migration and connectivity of mouse precerebellar neurons.

Science 2013 Jan;339(6116):204-7

Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland.

We investigated the role of histone methyltransferase Ezh2 in tangential migration of mouse precerebellar pontine nuclei, the main relay between neocortex and cerebellum. By counteracting the sonic hedgehog pathway, Ezh2 represses Netrin1 in dorsal hindbrain, which allows normal pontine neuron migration. In Ezh2 mutants, ectopic Netrin1 derepression results in abnormal migration and supernumerary nuclei integrating in brain circuitry. Moreover, intrinsic topographic organization of pontine nuclei according to rostrocaudal progenitor origin is maintained throughout migration and correlates with patterned cortical input. Ezh2 maintains spatially restricted Hox expression, which, in turn, regulates differential expression of the repulsive receptor Unc5b in migrating neurons; together, they generate subsets with distinct responsiveness to environmental Netrin1. Thus, Ezh2-dependent epigenetic regulation of intrinsic and extrinsic transcriptional programs controls topographic neuronal guidance and connectivity in the cortico-ponto-cerebellar pathway.
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http://dx.doi.org/10.1126/science.1229326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4824054PMC
January 2013

Hox10 genes function in kidney development in the differentiation and integration of the cortical stroma.

PLoS One 2011 16;6(8):e23410. Epub 2011 Aug 16.

Department of Internal Medicine, Division of Molecular Medicine and Genetics University of Michigan, Ann Arbor, Michigan, United States of America.

Organogenesis requires the differentiation and integration of distinct populations of cells to form a functional organ. In the kidney, reciprocal interactions between the ureter and the nephrogenic mesenchyme are required for organ formation. Additionally, the differentiation and integration of stromal cells are also necessary for the proper development of this organ. Much remains to be understood regarding the origin of cortical stromal cells and the pathways involved in their formation and function. By generating triple mutants in the Hox10 paralogous group genes, we demonstrate that Hox10 genes play a critical role in the developing kidney. Careful examination of control kidneys show that Foxd1-expressing stromal precursor cells are first observed in a cap-like pattern anterior to the metanephric mesenchyme and these cells subsequently integrate posteriorly into the kidney periphery as development proceeds. While the initial cap-like pattern of Foxd1-expressing cortical stromal cells is unaffected in Hox10 mutants, these cells fail to become properly integrated into the kidney, and do not differentiate to form the kidney capsule. Consistent with loss of cortical stromal cell function, Hox10 mutant kidneys display reduced and aberrant ureter branching, decreased nephrogenesis. These data therefore provide critical novel insights into the cellular and genetic mechanisms governing cortical cell development during kidney organogenesis. These results, combined with previous evidence demonstrating that Hox11 genes are necessary for patterning the metanephric mesenchyme, support a model whereby distinct populations in the nephrogenic cord are regulated by unique Hox codes, and that differential Hox function along the AP axis of the nephrogenic cord is critical for the differentiation and integration of these cell types during kidney organogenesis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0023410PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3156768PMC
February 2012