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1.
J Cell Biol ; 185(4): 713-25, 2009 May 18.
Article in English | MEDLINE | ID: mdl-19451277

ABSTRACT

Bone morphogenic protein (BMP) signaling is essential for the coordinated assembly of the synapse, but we know little about how BMP signaling is modulated in neurons. Our findings indicate that the Nemo (Nmo) kinase modulates BMP signaling in motor neurons. nmo mutants show synaptic structural defects at the Drosophila melanogaster larval neuromuscular junction, and providing Nmo in motor neurons rescues these defects. We show that Nmo and the BMP transcription factor Mad can be coimmunoprecipitated and find a genetic interaction between nmo and Mad mutants. Moreover, we demonstrate that Nmo is required for normal distribution and accumulation of phosphorylated Mad in motor neurons. Finally, our results indicate that Nmo phosphorylation of Mad at its N terminus, distinct from the BMP phosphorylation site, is required for normal function of Mad. Based on our findings, we propose a model in which phosphorylation of Mad by Nmo ensures normal accumulation and distribution of Mad and thereby fine tunes BMP signaling in motor neurons.


Subject(s)
DNA-Binding Proteins/physiology , Drosophila Proteins/physiology , Mitogen-Activated Protein Kinases/physiology , Neuromuscular Junction , Synapses , Transcription Factors/physiology , Animals , Bone Morphogenetic Proteins/metabolism , DNA-Binding Proteins/metabolism , Drosophila Proteins/metabolism , Drosophila melanogaster , Mitogen-Activated Protein Kinases/metabolism , Motor Neurons , Phosphorylation , Transcription Factors/metabolism
2.
Physiol Genomics ; 21(1): 112-6, 2005 Mar 21.
Article in English | MEDLINE | ID: mdl-15632271

ABSTRACT

Linkage studies suggested that a quantitative trait locus (QTL) for blood pressure (BP) was present in a region on chromosome 17 (Chr 17) of Dahl salt-sensitive (DSS) rats. A subsequent congenic strain targeting this QTL, however, could not confirm it. These conflicting results called into question the validity of localization of a QTL by linkage followed by the use of a congenic strain made with an incomplete chromosome coverage. To resolve this issue, we constructed five new congenic strains, designated C17S.L1 to C17S.L5, that completely spanned the +/-2 LOD confidence interval supposedly containing the QTL. Each congenic strain was made by replacing a segment of the DSS rat by that of the normotensive Lewis (LEW) rat. The only section to be LL homozygous is the region on Chr 17 specified in a congenic strain, as evidenced by a total genome scan. The results showed that BPs of C17S.L1 and C17S.L2 were lower (P < 0.04) than that of DSS rats. In contrast, BPs of C17S.L3, C17S.L4, and C17S.L5 were not different (P > 0.6) from that of DSS rats. Consequently, a BP QTL must be located in an interval of approximately 15 cM shared between C17S.L1 and C17S.L2 and unique to them both, as opposed to C17S.L3, C17S.L4, and C17S.L5. The present study illustrates the importance of thorough chromosome coverage, the necessity for a genome-wide screening, and the use of "negative" controls in physically mapping a QTL by congenic strains.


Subject(s)
Blood Pressure/genetics , Hypertension/genetics , Animals , Animals, Congenic , Chromosome Mapping , Chromosomes/ultrastructure , Genetic Linkage , Genetic Markers , Genetic Predisposition to Disease , Genome , Homozygote , Lod Score , Models, Genetic , Models, Statistical , Quantitative Trait Loci , Quantitative Trait, Heritable , Rats , Rats, Inbred Dahl
3.
Hypertens Res ; 27(3): 203-12, 2004 Mar.
Article in English | MEDLINE | ID: mdl-15080379

ABSTRACT

Chromosomes (Chr) 10 and 16 of the Dahl salt-sensitive (S) rat harbor quantitative trait loci (QTLs) for blood pressure (BP). To facilitate gene discovery of these QTLs, gene profiling based on microarrays was combined with fine QTL mapping to identify potential candidate genes that are differentially expressed. First, the region harboring the BP QTL on Chr 16 was narrowed by comparative congenic mapping. In this endeavor, a number of new chromosome markers were generated and used to physically define the chromosome interval in question. Second, in an effort to minimize the costs of gene profiling without sacrificing the chance of gene discovery, a combination congenic strain was produced by replacing one segment of Chr 10 along with one segment of Chr 16 of the hypertensive S rat by those of the normotensive Lewis (LEW) rat. Both of these regions are known to contain BP QTLs. Third, kidneys of this combination congenic strain and the S strain were employed for expression profiling studies. Finally, a comparison between the two strains yielded a number of potentially differentially expressed candidates. Six Established Sequence Tags (ESTs)/genes among them were located in Chr 10 regions and 1 was found in a Chr 16 region, and the genetic make-ups of all these regions were shown to be different between S and LEW. However, none of these ESTs/genes identified by gene profiling were located in an interval containing a QTL. Thus, the present study highlights the importance of correlating the results of gene expression profiling with fine congenic mapping.


Subject(s)
Blood Pressure/genetics , Gene Expression Profiling , Quantitative Trait Loci , Animals , Animals, Congenic , Chromosomes/genetics , Expressed Sequence Tags , Genetic Markers , Male , Oligonucleotide Array Sequence Analysis , Rats , Rats, Inbred Dahl , Rats, Inbred Lew
4.
Mamm Genome ; 13(3): 153-6, 2002 Mar.
Article in English | MEDLINE | ID: mdl-11919686

ABSTRACT

A Chromosome (Chr) 16 segment of the Dahl salt-sensitive (S) rat was shown by linkage to contain a blood pressure (BP) quantitative trait locus (QTL). To verify and further narrow down the region harboring the QTL, we made two congenic strains by replacing two segments of the S rats with the homologous segments of the Lewis (LEW) rats. The construction of these congenic strains was facilitated by a genome-wide marker screening. The two congenic strains contained a segment in common, and BPs of both were significantly lower than that of the S strain. Consequently, a BP QTL could be localized to the overlapping region of about 49.4 centiRay (cR) including the telomere on a radiation hybrid map. Heart weights, left and right ventricular weights, kidney weights, and aortic weights over length were all significantly decreased in the congenic strains compared with the S strain. Thus, there appeared to exist an association between the effects of the QTL on BP and on cardiac, renal, and vascular hypertrophy.


Subject(s)
Blood Pressure/genetics , Chromosome Mapping , Quantitative Trait, Heritable , Animals , Animals, Congenic , Rats , Rats, Inbred Dahl
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