Publications by authors named "Bruce J Herron"

18 Publications

  • Page 1 of 1

Multidimensional Genetic Analysis of Repeated Seizures in the Hybrid Mouse Diversity Panel Reveals a Novel Epileptogenesis Susceptibility Locus.

G3 (Bethesda) 2017 08 7;7(8):2545-2558. Epub 2017 Aug 7.

Wadsworth Center, New York State Department of Health, Albany, New York 12201

Epilepsy has many causes and comorbidities affecting as many as 4% of people in their lifetime. Both idiopathic and symptomatic epilepsies are highly heritable, but genetic factors are difficult to characterize among humans due to complex disease etiologies. Rodent genetic studies have been critical to the discovery of seizure susceptibility loci, including mutations identified in both mouse and human cohorts. However, genetic analyses of epilepsy phenotypes in mice to date have been carried out as acute studies in seizure-naive animals or in Mendelian models of epilepsy, while humans with epilepsy have a history of recurrent seizures that also modify brain physiology. We have applied a repeated seizure model to a genetic reference population, following seizure susceptibility over a 36-d period. Initial differences in generalized seizure threshold among the Hybrid Mouse Diversity Panel (HMDP) were associated with a well-characterized seizure susceptibility locus found in mice: Remarkably, influence diminished as subsequent induced seizures had diminishing latencies in certain HMDP strains. Administration of eight seizures, followed by an incubation period and an induced retest seizure, revealed novel associations within the calmodulin-binding transcription activator 1, Using systems genetics, we have identified four candidate genes that are differentially expressed between seizure-sensitive and -resistant strains close to our novel () locus that may act individually or as a coordinated response to the neuronal stress of seizures.
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http://dx.doi.org/10.1534/g3.117.042234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5555461PMC
August 2017

Divergence and inheritance of neocortical heterotopia in inbred and genetically-engineered mice.

Neurosci Lett 2017 01 18;638:175-180. Epub 2016 Dec 18.

Department of Biomedical Sciences, New York Institute of Technology College of Osteopathic Medicine, Old Westbury, NY 11568, United States. Electronic address:

Cortical function emerges from the intrinsic properties of neocortical neurons and their synaptic connections within and across lamina. Neurodevelopmental disorders affecting migration and lamination of the neocortex result in cognitive delay/disability and epilepsy. Molecular layer heterotopia (MLH), a dysplasia characterized by over-migration of neurons into layer I, are associated with cognitive deficits and neuronal hyperexcitability in humans and mice. The breadth of different inbred mouse strains that exhibit MLH and inheritance patterns of heterotopia remain unknown. A neuroanatomical survey of numerous different inbred mouse strains, 2 first filial generation (F1) hybrids, and one consomic strain (C57BL/6J-Chr 1/NaJ) revealed MLH only in C57BL/6 mice and the consomic strain. Heterotopia were observed in numerous genetically-engineered mouse lines on a congenic C57BL/6 background. These data indicate that heterotopia formation is a weakly penetrant trait requiring homozygosity of one or more C57BL/6 alleles outside of chromosome 1. These data are relevant toward understanding neocortical development and disorders affecting neocortical lamination.
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http://dx.doi.org/10.1016/j.neulet.2016.12.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5239770PMC
January 2017

Eight Flurothyl-Induced Generalized Seizures Lead to the Rapid Evolution of Spontaneous Seizures in Mice: A Model of Epileptogenesis with Seizure Remission.

J Neurosci 2016 07;36(28):7485-96

Departments of Neuroscience and Experimental Therapeutics, and Neurology, Albany Medical College, Albany, New York 12208,

Unlabelled: The occurrence of recurrent, unprovoked seizures is the hallmark of human epilepsy. Currently, only two-thirds of this patient population has adequate seizure control. New epilepsy models provide the potential for not only understanding the development of spontaneous seizures, but also for testing new strategies to treat this disorder. Here, we characterize a primary generalized seizure model of epilepsy following repeated exposure to the GABAA receptor antagonist, flurothyl, in which mice develop spontaneous seizures that remit within 1 month. In this model, we expose C57BL/6J mice to flurothyl until they experience a generalized seizure. Each of these generalized seizures typically lasts <30 s. We induce one seizure per day for 8 d followed by 24 h video-electroencephalographic recordings. Within 1 d following the last of eight flurothyl-induced seizures, ∼50% of mice have spontaneous seizures. Ninety-five percent of mice tested have seizures within the first week of the recording period. Of the spontaneous seizures recorded, the majority are generalized clonic seizures, with the remaining 7-12% comprising generalized clonic seizures that transition into brainstem seizures. Over the course of an 8 week recording period, spontaneous seizure episodes remit after ∼4 weeks. Overall, the repeated flurothyl paradigm is a model of epileptogenesis with spontaneous seizures that remit. This model provides an additional tool in our armamentarium for understanding the mechanisms underlying epileptogenesis and may provide insights into why spontaneous seizures remit without anticonvulsant treatment. Elucidating these processes could lead to the development of new epilepsy therapeutics.

Significance Statement: Epilepsy is a chronic disorder characterized by the occurrence of recurrent, unprovoked seizures in which the individual seizure-ictal events are self-limiting. Remission of recurrent, unprovoked seizures can be achieved in two-thirds of cases by treatment with anticonvulsant medication, surgical resection, and/or nerve/brain electrode stimulation. However, there are examples in humans of epilepsy with recurrent, unprovoked seizures remitting without any intervention. While elucidating how recurrent, unprovoked seizures develop is critical for understanding epileptogenesis, an understanding of how and why recurrent, unprovoked seizures remit may further our understanding and treatment of epilepsy. Here, we describe a new model of recurrent, unprovoked spontaneous seizures in which the occurrence of spontaneous seizures naturally remits over time without any therapeutic intervention.
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http://dx.doi.org/10.1523/JNEUROSCI.3232-14.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4945668PMC
July 2016

Angiogenesis QTL on Mouse Chromosome 8 Colocalizes with Differential β-Defensin Expression.

J Biomol Tech 2015 Jul;26(2):45-53

1 Wadsworth Center, New York State Department of Health, Albany, New York, USA; and 2 Department of Biomedical Sciences, School of Public Health, State University of New York at Albany, Albany, New York, USA.

Identification of genetic factors that modify complex traits is often complicated by gene-environment interactions that contribute to the observed phenotype. In model systems, the phenotypic outcomes quantified are typically traits that maximize observed variance, which in turn, should maximize the detection of quantitative trait loci (QTL) in subsequent mapping studies. However, when the observed trait is dependent on multiple interacting factors, it can complicate genetic analysis, reducing the likelihood that the modifying mutation will ultimately be found. Alternatively, by focusing on intermediate phenotypes of a larger condition, we can reduce a model's complexity, which will, in turn, limit the number of QTL that contribute to variance. We used a novel method to follow angiogenesis in mice that reduces environmental variance by measuring endothelial cell growth from culture of isolated skin biopsies that varies depending on the genetic source of the tissue. This method, in combination with a backcross breeding strategy, is intended to reduce genetic complexity and limit the phenotypic effects to fewer modifier loci. We determined that our approach was an efficient means to generate recombinant progeny and used this cohort to map a novel s.c. angiogenesis QTL to proximal mouse chromosome (Chr.) 8 with suggestive QTL on Chr. 2 and 7. Global mRNA expression analysis of samples from parental reference strains revealed β-defensins as potential candidate genes for future study.
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http://dx.doi.org/10.7171/jbt.15-2602-002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4365986PMC
July 2015

Spatiotemporal differences in the c-fos pathway between C57BL/6J and DBA/2J mice following flurothyl-induced seizures: A dissociation of hippocampal Fos from seizure activity.

Epilepsy Res 2015 Jan 22;109:183-96. Epub 2014 Nov 22.

Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, NY 12208, USA; Department of Biology, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180, USA; Department of Neurology, Albany Medical College, Albany, NY 12208, USA. Electronic address:

Significant differences in seizure characteristics between inbred mouse strains highlight the importance of genetic predisposition to epilepsy. Here, we examined the genetic differences between the seizure-resistant C57BL/6J (B6) mouse strain and the seizure-susceptible DBA/2J (D2) strain in the phospho-Erk and Fos pathways to examine seizure-induced neuronal activity to uncover potential mechanistic correlates to these disparate seizure responsivities. Expression of neural activity markers was examined following 1, 5, or 8 seizures, or after 8 seizures, a 28 day rest period, and a final flurothyl rechallenge. Two brain regions, the hippocampus and ventromedial nucleus of the hypothalamus (VMH), had significantly different Fos expression profiles following seizures. Fos expression was highly robust in B6 hippocampus following one seizure and remained elevated following multiple seizures. Conversely, there was an absence of Fos (and phospho-Erk) expression in D2 hippocampus following one generalized seizure that increased with multiple seizures. This lack of Fos expression occurred despite intracranial electroencephalographic recordings indicating that the D2 hippocampus propagated ictal discharge during the first flurothyl seizure suggesting a dissociation of seizure discharge from Fos and phospho-Erk expression. Global transcriptional analysis confirmed a dysregulation of the c-fos pathway in D2 mice following 1 seizure. Moreover, global analysis of RNA expression differences between B6 and D2 hippocampus revealed a unique pattern of transcripts that were co-regulated with Fos in D2 hippocampus following 1 seizure. These expression differences could, in part, account for D2's seizure susceptibility phenotype. Following 8 seizures, a 28 day rest period, and a final flurothyl rechallenge, ∼85% of B6 mice develop a more complex seizure phenotype consisting of a clonic-forebrain seizure that uninterruptedly progresses into a brainstem seizure. This seizure phenotype in B6 mice is highly correlated with bilateral Fos expression in the VMH and was not observed in D2 mice, which always express clonic-forebrain seizures upon flurothyl retest. Overall, these results illustrate specific differences in protein and RNA expression in different inbred strains following seizures that precede the reorganizational events that affect seizure susceptibility and changes in seizure semiology over time.
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http://dx.doi.org/10.1016/j.eplepsyres.2014.11.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4272448PMC
January 2015

Mapping Novel Subcutaneous Angiogenesis Quantitative Trait Loci in [B6×MRL]F2 Mice.

Adv Wound Care (New Rochelle) 2014 Sep;3(9):563-572

Wadsworth Center , NYS Department of Health, Albany, New York. ; School of Public Health, State University of New York at Albany , Albany, New York.

MRL/MpJ mice are known for enhanced healing, but mechanistic details or how specific aspects of wounding (., angiogenesis) contribute to healing are unknown. While previous studies investigated the systemic effects of immunity in MRL/MpJ healing, few have focused on tissue-intrinsic effects. skin biopsies from MRL/MpJ and C57BL/6J mice were cultured in conditions that favor endothelial cell growth to compare their angiogenic potential. We localized enhanced angiogenesis quantitative trait loci (QTL) in an F2 intercross. We then performed an expression analysis in cultured skin biopsies from MRL/MpJ and C57BL/6J mice to determine the pathways that are associated with the capacity for differential growth. MRL/MpJ biopsies have a two- to threefold greater growth potential than C57BL/6J mice, supporting the hypothesis that angiogenesis may contribute to enhanced healing in MRL/MpJ skin. We mapped two QTLs that are unique from previously mapped MRL/MpJ wound healing QTLs and detected interactions between wound healing QTLs and loci in this cross. Additionally, we found that pathways previously implicated in MRL/MpJ healing are also enriched in skin biopsies. We have developed a novel approach to determine how specific aspects of tissue development contribute to wound healing that will ultimately lead to the discovery of unidentified genes that contribute to enhanced healing. We have shown that, consistent with previous studies following wound closure in MRL/MpJ mice, vessel growth during healing is also influenced by genetic background. Our ongoing work will identify the genetic factors that should be useful biomarkers or as therapeutic targets for enhanced wound healing.
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http://dx.doi.org/10.1089/wound.2013.0501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4152795PMC
September 2014

Segregation of seizure traits in C57 black mouse substrains using the repeated-flurothyl model.

PLoS One 2014 3;9(3):e90506. Epub 2014 Mar 3.

Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, New York, United States of America; Department of Neurology, Albany Medical College, Albany, New York, United States of America.

Identifying the genetic basis of epilepsy in humans is difficult due to its complexity, thereby underlying the need for preclinical models with specific aspects of seizure susceptibility that are tractable to genetic analyses. In the repeated-flurothyl model, mice are given 8 flurothyl-induced seizures, once per day (the induction phase), followed by a 28-day rest period (incubation phase) and final flurothyl challenge. This paradigm allows for the tracking of multiple phenotypes including: initial generalized seizure threshold, decreases in generalized seizure threshold with repeated flurothyl exposures, and changes in the complexity of seizures over time. Given the responses we previously reported in C57BL/6J mice, we analyzed substrains of the C57BL lineage to determine if any of these phenotypes segregated in these substrains. We found that the generalized seizure thresholds of C57BL/10SNJ and C57BL/10J mice were similar to C57BL/6J mice, whereas C57BL/6NJ and C57BLKS/J mice showed lower generalized seizure thresholds. In addition, C57BL/6J mice had the largest decreases in generalized seizure thresholds over the induction phase, while the other substrains were less pronounced. Notably, we observed only clonic seizures during the induction phase in all substrains, but when rechallenged with flurothyl after a 28-day incubation phase, ∼80% of C57BL/6J and 25% of C57BL/10SNJ and C57BL/10J mice expressed more complex seizures with tonic manifestations with none of the C57BL/6NJ and C57BLKS/J mice having complex seizures with tonic manifestations. These data indicate that while closely related, the C57BL lineage has significant diversity in aspects of epilepsy that are genetically controlled. Such differences further highlight the importance of genetic background in assessing the effects of targeted deletions of genes in preclinical epilepsy models.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0090506PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3940897PMC
November 2014

Genetic heterogeneity of skin microvasculature.

Dev Biol 2010 Apr 17;340(2):480-9. Epub 2010 Feb 17.

Wadsworth Center, NYS Department of Health, Albany, NY 12201, USA.

Angiogenesis, the formation of new blood vessels from existing vasculature, is a complex process that is essential for normal embryonic development. Current models for experimental evaluation of angiogenesis often use tissue from large vessels like the aorta and umbilical vein, which are phenotypically distinct from microvasculature. We demonstrate that the utilization of skin to measure microvascular angiogenesis in embryonic and adult tissues is an efficient way to quantify microvasculature angiogenesis. We validate this approach and demonstrate its added value by showing significant differences in angiogenesis in monogenic and polygenic mouse models. We discovered that the pattern of angiogenic response among inbred mouse strains in this ex vivo assay differs from the strain distributions of previous in vivo angiogenesis assays. The difference between the ex vivo and in vivo assays may be related to systemic factors present in whole animals. Expression analysis of cultured skin biopsies from strains of mice with opposing angiogenic response was performed to identify pathways that contribute to differential angiogenic response. Increased expression of negative regulators of angiogenesis in C57Bl/6J mice was associated with lower growth rates.
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http://dx.doi.org/10.1016/j.ydbio.2010.02.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2854179PMC
April 2010

Prdm16 is required for normal palatogenesis in mice.

Hum Mol Genet 2010 Mar 11;19(5):774-89. Epub 2009 Dec 11.

Genetics Division, Brigham and Women's Hospital, Harvard Medical School, New Research Building, Boston, MA 02115, USA.

Transcriptional cofactors are essential to the regulation of transforming growth factor beta (TGFbeta) superfamily signaling and play critical and widespread roles during embryonic development, including craniofacial development. We describe the cleft secondary palate 1 (csp1) N-ethyl-N-nitrosourea-induced mouse model of non-syndromic cleft palate (NSCP) that is caused by an intronic Prdm16 splicing mutation. Prdm16 encodes a transcriptional cofactor that regulates TGFbeta signaling, and its expression pattern is consistent with a role in palate and craniofacial development. The cleft palate (CP) appears to be the result of micrognathia and failed palate shelf elevation due to physical obstruction by the tongue, resembling human Pierre Robin sequence (PRS)-like cleft secondary palate. PRDM16 should be considered a candidate for mutation in human clefting disorders, especially NSCP and PRS-like CP.
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http://dx.doi.org/10.1093/hmg/ddp543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2816611PMC
March 2010

Analysis of flurothyl-induced myoclonus in inbred strains of mice.

Epilepsy Res 2009 Dec 9;87(2-3):130-6. Epub 2009 Sep 9.

Department of Biology, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180, USA.

Myoclonus is often observed in epilepsy. It is characterized by sudden involuntary shock-like movements of the body (myoclonic jerks, MJs). This study examined whether epileptic myoclonus was under genetic control. Inbred strains of mice were administered eight daily flurothyl exposures, a 28-day rest period, and a final flurothyl retest. For all trials, the latency to the first MJ (threshold) and the number of MJs (MJ#) were recorded. The inbred strains that we examined exhibited significant variability in initial myoclonic response, and myoclonus across the eight flurothyl exposures. C57BL/6J and DBA/2J mice displayed significantly different initial latencies to a MJ, MJ# preceding a generalized seizure (GS), and changes in MJ threshold and MJ# across the eight seizure trials. [C57BL/6J x DBA/2J] F1-hybrid mice showed an initial MJ threshold and decreases in MJ threshold over the eight trials, which were similar to C57BL/6J; however, F1-hybrids had an initial MJ# and trend in MJ# over the eight trials that were similar to DBA/2J. Decreases in MJ threshold and MJ# following multiple seizure trials, observed in C57BL/6J mice, were dependent on the expression of GSs and not on MJ occurrence. Our study is the first to document the potential for genetic heterogeneity of myoclonus in mice; we show that significant alterations in myoclonic behavior occur after GSs. These results indicate that multiple GSs affect MJ thresholds. An understanding of the genetics of myoclonus will be important for determination of the brain areas responsible for myoclonus as well as for identification of candidate genes.
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http://dx.doi.org/10.1016/j.eplepsyres.2009.08.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2788057PMC
December 2009

Dissociation of seizure traits in inbred strains of mice using the flurothyl kindling model of epileptogenesis.

Exp Neurol 2009 Jan 7;215(1):60-8. Epub 2008 Oct 7.

Department of Biology, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180, USA.

Previous seizure models have demonstrated genetic differences in generalized seizure threshold (GST) in inbred mice, but the genetic control of epileptogenesis is relatively unexplored. The present study examined, through analysis of inbred strains of mice, whether the seizure characteristics observed in the flurothyl kindling model are under genetic control. Eight consecutive, daily generalized seizures were induced by flurothyl in mice from five inbred strains. Following a 28-day rest period, mice were retested with flurothyl. The five strains of mice demonstrated inter-strain differences in GST, decreases in GST across seizure trials, and differences in the behavioral seizure phenotypes expressed. Since many of the seizure characteristics that we examined in the flurothyl kindling model were dissociable between C57BL/6J and DBA/2J mice, we analyzed these strains in detail. Unlike C57BL/6J mice, DBA/2J mice had a lower GST on trial 1, did not demonstrate a decrease in GST across trials, nor did they show an alteration in seizure phenotype upon flurothyl retest. Surprisingly, [C57BL/6JxDBA/2J] F1-hybrids had initial GST on trial 1 and GST decreases across trials similar to what was found for C57BL/6J, but they did not undergo the alteration in behavioral seizure phenotype that had been observed for C57BL/6J mice. Our data establish the significance of the genetic background in flurothyl-induced epileptogenesis. The [C57BL/6JxDBA/2J] F1-hybrid data demonstrate that initial GST, the decrease in GST across trials, and the change in seizure phenotype differ from the characteristics of the parental strains, suggesting that these phenotypes are controlled by independent genetic loci.
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http://dx.doi.org/10.1016/j.expneurol.2008.09.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2656999PMC
January 2009

THM1 negatively modulates mouse sonic hedgehog signal transduction and affects retrograde intraflagellar transport in cilia.

Nat Genet 2008 Apr 9;40(4):403-410. Epub 2008 Mar 9.

Genetics Division, Brigham and Women's Hospital, Harvard Medical School, New Research Building, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.

Characterization of previously described intraflagellar transport (IFT) mouse mutants has led to the proposition that normal primary cilia are required for mammalian cells to respond to the sonic hedgehog (SHH) signal. Here we describe an N-ethyl-N-nitrosourea-induced mutant mouse, alien (aln), which has abnormal primary cilia and shows overactivation of the SHH pathway. The aln locus encodes a novel protein, THM1 (tetratricopeptide repeat-containing hedgehog modulator-1), which localizes to cilia. aln-mutant cilia have bulb-like structures at their tips in which IFT proteins (such as IFT88) are sequestered, characteristic of Chlamydomonas reinhardtii and Caenorhabditis elegans retrograde IFT mutants. RNA-interference knockdown of Ttc21b (which we call Thm1 and which encodes THM1) in mouse inner medullary collecting duct cells expressing an IFT88-enhanced yellow fluorescent protein fusion recapitulated the aln-mutant cilial phenotype, and live imaging of these cells revealed impaired retrograde IFT. In contrast to previously described IFT mutants, Smoothened and full-length glioblastoma (GLI) proteins localize to aln-mutant cilia. We hypothesize that the aln retrograde IFT defect causes sequestration of IFT proteins in aln-mutant cilia and leads to the overactivated SHH signaling phenotype. Specifically, the aln mutation uncouples the roles of anterograde and retrograde transport in SHH signaling, suggesting that anterograde IFT is required for GLI activation and that retrograde IFT modulates this event.
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http://dx.doi.org/10.1038/ng.105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4817720PMC
April 2008

A mutation in stratifin is responsible for the repeated epilation (Er) phenotype in mice.

Nat Genet 2005 Nov 2;37(11):1210-2. Epub 2005 Oct 2.

Genomics Institute, Wadsworth Center, NYS Dept. of Health, 465 Jordan Road, Albany, New York 12180, USA.

Stratifin (Sfn, also called 14-3-3sigma) is highly expressed in differentiating epidermis and mediates cell cycle arrest. Sfn is repressed in cancer, but its function during development is uncharacterized. We identified an insertion mutation in the gene Sfn in repeated epilation (Er) mutant mice by positional cloning. Er/+ mice expressed a truncated Sfn protein, which probably contributes to the defects in Er/Er and Er/+ epidermis and to cancer development in Er/+ mice.
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http://dx.doi.org/10.1038/ng1652DOI Listing
November 2005

Fog2 is required for normal diaphragm and lung development in mice and humans.

PLoS Genet 2005 Jul 17;1(1):58-65. Epub 2005 Jun 17.

Division of Emergency Medicine, Department of Medicine, Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

Congenital diaphragmatic hernia and other congenital diaphragmatic defects are associated with significant mortality and morbidity in neonates; however, the molecular basis of these developmental anomalies is unknown. In an analysis of E18.5 embryos derived from mice treated with N-ethyl-N-nitrosourea, we identified a mutation that causes pulmonary hypoplasia and abnormal diaphragmatic development. Fog2 (Zfpm2) maps within the recombinant interval carrying the N-ethyl-N-nitrosourea-induced mutation, and DNA sequencing of Fog2 identified a mutation in a splice donor site that generates an abnormal transcript encoding a truncated protein. Human autopsy cases with diaphragmatic defect and pulmonary hypoplasia were evaluated for mutations in FOG2. Sequence analysis revealed a de novo mutation resulting in a premature stop codon in a child who died on the first day of life secondary to severe bilateral pulmonary hypoplasia and an abnormally muscularized diaphragm. Using a phenotype-driven approach, we have established that Fog2 is required for normal diaphragm and lung development, a role that has not been previously appreciated. FOG2 is the first gene implicated in the pathogenesis of nonsyndromic human congenital diaphragmatic defects, and its necessity for pulmonary development validates the hypothesis that neonates with congenital diaphragmatic hernia may also have primary pulmonary developmental abnormalities.
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http://dx.doi.org/10.1371/journal.pgen.0010010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1183529PMC
July 2005

A mutation in NFkB interacting protein 1 results in cardiomyopathy and abnormal skin development in wa3 mice.

Hum Mol Genet 2005 Mar 20;14(5):667-77. Epub 2005 Jan 20.

Genetics Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.

We have identified waved 3 (wa3), a novel recessive mutation that causes abnormalities of the heart and skin. The cardiac defect results in a severe and rapidly progressive dilated cardiomyopathy. We identified the gene mutated in these mice, which we call NFkB interacting protein1 (Nkip1), using positional cloning. Nkip1 is expressed in skin, heart and vascular endothelium and shares homology with a small family of proteins that play a role in the regulation of transcription factors. A C-terminal fragment of this protein was previously identified as the RelA associated inhibitor (RAI). We show that the full-length protein is larger than previously described, and we confirm that it interacts with NFkB in vivo. Expression analysis of genes known to be regulated by NFkB revealed that Intercellular adhesion molecule 1 (Icam1) expression is consistently elevated in mutant mice. This result suggests that wa3 mutant mice represent a potentially important model for the analysis of the role of inflammatory processes in heart disease.
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http://dx.doi.org/10.1093/hmg/ddi063DOI Listing
March 2005

Genetic mapping and ENU mutagenesis.

Genetica 2004 Sep;122(1):65-9

Genetics Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

ENU mutagenesis is a potent means to generate novel mutations in the mouse, and the further investigation of these mutations can be logistically demanding. Determination of the map position of a mutation early in its characterization can be extremely useful. We describe how the use of interval haplotype analysis can facilitate this with even small numbers of affected progeny.
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http://dx.doi.org/10.1007/s10709-004-1437-5DOI Listing
September 2004

2001: a mouse genome odyssey.

Genome Biol 2002 31;3(2):REPORTS4005. Epub 2002 Jan 31.

Genetics Division, Brigham and Women's Hospital and Harvard Medical School, 20 Shattuck St, Boston, MA 02115, USA.

A report on the 15th International Mouse Genome Conference, Edinburgh, UK, 21-24 October 2001.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC139011PMC
http://dx.doi.org/10.1186/gb-2002-3-2-reports4005DOI Listing
June 2002

Efficient generation and mapping of recessive developmental mutations using ENU mutagenesis.

Nat Genet 2002 Feb 2;30(2):185-9. Epub 2002 Jan 2.

Genetics Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.

Treatment with N-ethyl-N-nitrosourea (ENU) efficiently generates single-nucleotide mutations in mice. Along with the renewed interest in this approach, much attention has been given recently to large screens with broad aims; however, more finely focused studies have proven very productive as well. Here we show how mutagenesis together with genetic mapping can facilitate the rapid characterization of recessive loci required for normal embryonic development. We screened third-generation progeny of mutagenized mice at embryonic day (E) 18.5 for abnormalities of organogenesis. We ascertained 15 monogenic mutations in the 54 families that were comprehensively analyzed. We carried out the experiment as an outcross, which facilitated the genetic mapping of the mutations by haplotype analysis. We mapped seven of the mutations and identified the affected locus in two lines. Using a hierarchical approach, it is possible to maximize the efficiency of this analysis so that it can be carried out easily with modest infrastructure and resources.
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http://dx.doi.org/10.1038/ng812DOI Listing
February 2002