Biomedical subjects

Hiroyuki Yamagishi

Publications and source records attributed to Hiroyuki Yamagishi.

At least 19 recordsLinked to original sources

PubMed2006

Persistent high levels of plasma oxidized low-density lipoprotein after acute myocardial infarction predict stent restenosis.

OBJECTIVE: Recently, elevated levels of plasma oxidized low-density lipoprotein (LDL) have been shown to relate to plaque instability in human atherosclerotic lesions. We investigated prospectively patients admitted with acute myocardial infarction (AMI) who underwent primary coronary stenting to evaluate whether the 6-month outcome could be predicted by measuring plasma oxidized LDL (ox-LDL) levels at the time of hospital discharge. METHODS AND RESULTS: Plasma ox-LDL levels were measured in 102 patients with AMI undergoing primary coronary stenting using a highly sensitive ELISA method. Measurements were taken on admission and at discharge, and the findings related to the clinical outcome. At 6-month follow-up, angiographic stent restenosis occurred in 25 (25%) of the 102 AMI patients. Plasma ox-LDL levels at discharge were significantly (P=0.0074) higher in the restenosis group than those in the no-restenosis group (1.03+/-0.65 versus 0.61+/-0.34 ng/5 microg LDL protein). Multiple regression analysis showed that only plasma ox-LDL levels at discharge were a statistically significant independent predictor for late lumen loss after stenting (beta=0.645; P<0.0001). CONCLUSIONS: This prospective study demonstrates that persistence of an increased level of plasma ox-LDL at discharge is a strong independent predictor of stent restenosis at 6-month follow-up in AMI patients.

Aged↗

PubMed2006

Tbx1 is regulated by forkhead proteins in the secondary heart field.

Transcriptional regulation in a tissue-specific and quantitative manner is essential for developmental events, including those involved in cardiovascular morphogenesis. Tbx1 is a T-box-containing transcription factor that is responsible for many of the defects observed in 22q11 deletion syndrome in humans. Tbx1 is expressed in the secondary heart field (SHF) and is essential for cardiac outflow tract (OFT) development. We previously reported that Tbx1 is regulated by sonic hedgehog by means of forkhead (Fox) transcription factors in the head mesenchyme and pharyngeal endoderm, but how it is regulated in the SHF is unknown. Here, we show that Tbx1 expression in the SHF is regulated by Fox proteins through a combination of two evolutionarily conserved Fox binding sites in a dose-dependent manner. Cell fate analysis using the Tbx1 enhancer suggests that SHF-derived Tbx1-expressing cells contribute extensively to the right ventricular myocardium as well as the OFT during early development and ultimately give rise to the right ventricular infundibulum, pulmonary trunk, and pulmonary valves. These results suggest that Fox proteins are involved in most, if not all, Tbx1 expression domains and that Tbx1 marks a subset of SHF-derived cells, particularly those that uniquely contribute to the right-sided outflow tract and proximal pulmonary artery.

Animals↗

PubMed2006

Acute myocardial infarction: clinical characteristics and plaque morphology between expansive remodeling and constrictive remodeling by intravascular ultrasound.

BACKGROUND: According to recent intravascular ultrasound (IVUS) studies, expansive remodeling (ER) at the culprit lesion has been observed in almost 50% of patients with acute coronary syndrome and constrictive remodeling (CR) in 30%. The purpose of this study is to investigate the difference between ER and CR at the culprit lesion in patients with acute myocardial infarction (AMI). METHODS AND RESULTS: Preinterventional IVUS images of 73 patients with AMI were identified. The remodeling index (RI) was defined as the ratio of the external elastic membrane (EEM) areas at the culprit lesion to the EEM areas at the proximal reference site. Expansive remodeling was defined as an RI > 1.05; CR, as an RI < 0.95. In patients with AMI, 40 patients (55%) showed ER on IVUS, whereas CR was observed in 18 patients (25%). Patients with ER were significantly older than those with CR (P < .005). The frequency of the presence of calcifications was higher in patients with ER than in those with CR (P < .0005). In patients with AMI with ER, soft plaque with small calcium was the most frequent (58%). Multivariate analysis revealed that age and the presence of calcifications remained as independent predictors of ER. CONCLUSIONS: These findings suggest that ER relates to old age and calcification, and CR may contribute to early plaque progression than ER in patients with AMI.

Age Factors↗

PubMed2006

Noninvasive diagnosis of restenosis by transthoracic Doppler echocardiography after percutaneous coronary intervention: comparison with exercise Tl-SPECT.

OBJECTIVE: Noninvasive methods that have the ability to accurately detect restenosis have been desired in the selection of patients requiring further angiographic evaluation. The present study sought to evaluate the diagnostic potential of transthoracic Doppler echocardiography (TTDE), a noninvasive method for evaluating coronary flow velocity reserve (CFVR), in detecting restenosis after percutaneous coronary intervention (PCI). METHODS: We studied 107 consecutive patients 6 months after undergoing successful PCI on the left anterior descending coronary artery (LAD) lesions for relief of angina pectoris. The flow velocity in the distal LAD was measured by TTDE both at rest and during intravenous infusion of adenosine triphosphate. CFVR was calculated as the ratio of hyperemic to basal mean diastolic flow velocities. We defined a reversible perfusion defect in exercise Tl-201 single-photon emission computed tomography (SPECT) as restenosis. The CFVR measurements by TTDE were compared with the results of SPECT. RESULTS: Complete TTDE data were acquired for 105 of the 107 study patients. A contrast agent was used to obtain adequate Doppler signals in 29 patients. Of the 105 patients, there were 18 patients with abnormal perfusion (group A) and 87 patients with normal perfusion (group B) in the LAD territories on Tl-201 SPECT. CFVR was greater in group B than in group A (1.7 +/- 0.5 vs. 3.7 +/- 0.8, P < 0.0001, respectively). There were 17 patients with CFVR < 2 and 88 patients with CFVR > or = 2. CFVR < 2 predicted restenosis determined by Tl-201 SPECT, with a sensitivity of 94% and a specificity of 100%. CONCLUSIONS: Noninvasive measurement of CFVR by TTDE accurately reflects the physiological severity of coronary narrowing due to restenosis after PCI. This method has possibility of reducing the number of unnecessary coronary angiographies after PCI.

Angioplasty, Balloon, Coronary↗

PubMed2006

Coronary flow velocity reserve measurement in three major coronary arteries using transthoracic Doppler echocardiography.

BACKGROUND: Measurement of the coronary flow velocity reserve (CFVR) by transthoracic Doppler echocardiography (TTDE) has been reported to be useful for the noninvasive assessment of significant coronary artery stenosis or myocardial ischemia. The purpose of this study was to evaluate the value of this method in three major coronary arteries for detecting myocardial ischemia in the clinical setting. METHODS: We studied 89 consecutive patients who were referred to our outpatient clinic because of chest pain. We measured CFVR using TTDE in three major coronary arteries. We defined CFVR<2.0 in at least one vessel as being positive for myocardial ischemia. The accuracy of CFVR measurements for detecting myocardial ischemia was determined in comparison with exercise thallium-201 (Tl-201) single photon emission computed tomography (SPECT) as a reference standard. RESULTS: CFVR in at least one vessel was successfully measured in 87 of 89 patients (98%). The sensitivity and specificity of CFVR<2.0 in at least one coronary vessel, in any of the coronary territories, was 86% and 89%, respectively. In terms of assessing myocardial ischemia in each coronary artery territory, the agreement between CFVR<2.0 and Tl-201 SPECT for the left anterior descending coronary artery, the posterior descending coronary artery, and the left circumflex coronary artery territories was 95%, 81%, and 73%, respectively. CONCLUSION: Noninvasive CFVR measurement by TTDE may be useful for detecting myocardial ischemia, as well as for identifying ischemic territories in the clinical setting.

Adenosine Triphosphate↗

PubMed2006

Sonic hedgehog is essential for first pharyngeal arch development.

The secreted protein sonic hedgehog (Shh) is essential for normal development of many organs. Targeted disruption of Shh in mouse leads to near complete absence of craniofacial skeletal elements at birth, and mutation of SHH in human causes holoprosencephaly (HPE), frequently associated with defects of derivatives of pharyngeal arches. To investigate the role of Shh signaling in early pharyngeal arch development, we analyzed Shh mutant embryos using molecular markers and found that the first pharyngeal arch (PA1) was specifically hypoplastic and fused in the midline, and remaining arches were well formed at embryonic day (E) 9.5. Molecular analyses using specific markers suggested that the growth of the maxillary arch and proximal mandibular arch was severely defective in Shh-null PA1, whereas the distal mandibular arch was less affected. TUNEL assay revealed an increase in the number of apoptotic signals in PA1 of Shh mutant embryos. Ectodermal expression of fibroblast growth factor (Fgf)-8, a cell survival factor for pharyngeal arch mesenchyme, was down-regulated in the PA1 of Shh mutants. Consistent with this observation, downstream transcriptional targets of Fgf8 signaling in neural crest-derived mesenchyme, including Barx1, goosecoid, and Dlx2, were also down-regulated in Shh-null PA1. These results demonstrate that epithelial-mesenchymal signaling and transcriptional events coordinated by Shh, partly via Fgf8, is essential for cell survival and tissue outgrowth of the developing PA1.

Animals↗

PubMed2005

Non-invasive assessment of myocardial ischaemia using new real-time three-dimensional dobutamine stress echocardiography: comparison with conventional two-dimensional methods.

AIMS: Although two-dimensional-dobutamine stress echocardiography (2D-DSE) is useful for the diagnosis of myocardial ischaemia, it requires the acquisition of multiple cross-sections at each stage. The introduction of new real-time three-dimensional echocardiography (RT3DE) offers rapid acquisition and 3D display of the entire left ventricle (LV). The purpose was to evaluate real-time three-dimensional-dobutamine stress echocardiography (RT3D-DSE) for the diagnosis of ischaemia using exercise (201)Tl single-photon emission computed tomography (SPECT) as the reference standard, in comparison with 2D-DSE. METHODS AND RESULTS: We performed DSE in 56 consecutive patients who had undergone SPECT because of suspected ischaemia. 3D images by RT3DE were acquired from the apical window after the acquisition of cross-sectional images at every stage of 2D-DSE. Wall motion analysis in RT3DE was performed from anatomical images by cropping the acquired full volume data sets. Mean scanning time for adequate image acquisition at peak stress by RT3D-DSE was shorter than that by 2D-DSE (29+/-4 vs. 68+/-6 s, P<0.0001). RT3DE provided adequate images at success rate of 92% at rest and 89% at peak stress, whereas two-dimensional echocardiography did at 94 and 90%, respectively. The sensitivity, specificity, and accuracy of RT3D-DSE for the detection of coronary artery disease are 86, 80, and 82%, respectively. Those of 2D-DSE are 86, 83, and 84%, respectively. There were no significant differences in the sensitivity, specificity, and accuracy between these two methods (P=1.000). CONCLUSION: RT3D-DSE offers rapid and simple acquisition of the entire LV wall motion and provides feasible and accurate assessment of myocardial ischaemia.

Aged↗

PubMed2005

Protective effect of high diastolic blood pressure during exercise against exercise-induced myocardial ischemia.

BACKGROUND: Hypertension is one of the risk factors for coronary artery disease. However, because most coronary blood flow to the left ventricle occurs during diastole, high diastolic blood pressure during exercise may have a protective effect against exercise-induced myocardial ischemia. The aim of the present study was to test this hypothesis. METHODS AND RESULTS: We identified 469 patients with sinus rhythm and known or suspected coronary artery disease who underwent exercise thallium-201 myocardial single-photon emission computed tomography and coronary arteriography. High diastolic blood pressure during exercise was defined as diastolic blood pressure at peak exercise > or = 90 mm Hg. There was no significant difference in medications, number of diseased vessels, or Gensini score between patients with high (n = 228) and normal (n = 241) diastolic blood pressure during exercise, whereas patients with high diastolic blood pressure during exercise exhibited a higher pressure-rate product during exercise than patients with normal diastolic blood pressure during exercise. The reversibility score on thallium-201 myocardial scan was significantly smaller in patients with high diastolic blood pressure during exercise than in patients with normal diastolic blood pressure during exercise (P = .021). CONCLUSIONS: High diastolic blood pressure during exercise has a potential protective effect against exercise-induced ischemia, although the mechanism of such effects remains to be determined.

Adult↗

PubMed2005

Physiologic assessment of coronary artery stenosis without stress tests: noninvasive analysis of phasic flow characteristics by transthoracic Doppler echocardiography.

We evaluated the significance of the diastolic-to-systolic blood flow velocity ratio (DSVR) determined by transthoracic Doppler echocardiography, for a physiologic assessment of the severity of coronary stenosis without stress tests, as compared with thallium 201 single photon emission computed tomography. In 95 patients undergoing thallium 201 single photon emission computed tomography for coronary artery disease, the flow velocity in the distal left anterior descending coronary artery was obtained with transthoracic Doppler echocardiography. The mean and peak DSVR values were calculated using mean and peak coronary flow velocity. DSVR was successfully measured for 82 patients (86.3%), including 33 patients with reversible perfusion defects in the left anterior descending coronary artery territories. For predicting reversible perfusion defects in thallium 201 single photon emission computed tomography, the best cut-off points were 1.5 for mean DSVR (sensitivity 81.8%, specificity 85.7%) and 1.6 for peak DSVR (sensitivity 75.7%, specificity 83.6%). Noninvasive measurement of DSVR with transthoracic Doppler echocardiography provides physiologic estimation of the left anterior descending coronary artery stenosis severity at high success rate, without stress tests.

Coronary Circulation↗

PubMed2005

Freehand three-dimensional echocardiography with rotational scanning for measurements of left ventricular volume and ejection fraction in patients with coronary artery disease.

BACKGROUND: Measurement of left ventricular (LV) volumes and ejection fraction (EF) is important in managing patients with coronary artery disease (CAD). Introduction of free-hand three-dimensional echocardiography (3DE) system which is equipped with small magnetic tracking system and average rotational geometry for LV volumes may provide easy and accurate quantification of LV systolic function in CAD patients. PURPOSE: To evaluate the feasibility and accuracy of LV volumes and EF measurement by free-hand 3DE with rotational geometry in patients with CAD. METHODS AND RESULTS: The study subjects consisted of consecutive 25 patients with CAD who were scheduled for quantitative gated single-photon emission computed tomography (QGS). LV end-diastolic volume (EDV), end-systolic volume (ESV), and EF were determined by conventional two-dimensional echocardiography (2DE), 3DE, and QGS. Three-dimensional echocardiography data acquisition and analysis were possible in 22 of 25 subjects (feasibility 88%). In this 3DE system, image acquisition time was 2 minutes, and 5 minutes were needed for off-line analysis of LV volumes and EF. Correlations and the limits of agreement between 3DE and QGS (r = 0.97, 0.0 +/- 9.1 ml for EDV, r = 0.99, 0.0 +/- 5.0 ml for ESV, and r = 0.97, 0.5 +/- 3.3% for EF, respectively) were superior to those between 2DE and QGS (r = 0.85, 12.6 +/- 26.8 ml for EDV, r = 0.85, 9.7 +/- 26.1 ml for ESV, and r = 0.90, -1.3 +/- 6.9% for EF, respectively). Inter- and intra-observer variabilities of 3DE were smaller than that of 2DE (5% vs 10%, 5% vs 10% for EDV, 6% vs 13%, 5% vs 9% for ESV, and 4% vs 11%, 4% vs 6% for EF, respectively). CONCLUSION: Three-dimensional echocardiography using magnetic tracking system and average rotational geometry offered a feasible and accurate method for quantification of LV volumes and EF in patients with CAD.

Aged↗

PubMed2004

Spotty calcification typifies the culprit plaque in patients with acute myocardial infarction: an intravascular ultrasound study.

BACKGROUND: Calcification is a common finding in human coronary arteries; however, the relationship between calcification patterns, plaque morphology, and patterns of remodeling of culprit lesions in a comparison of patients with acute coronary syndromes (ACS) and those with stable conditions has not been documented. METHODS AND RESULTS: Preinterventional intravascular ultrasound (IVUS) images of 178 patients were studied, 61 with acute myocardial infarction (AMI), 70 with unstable angina pectoris (UAP), and 47 with stable angina pectoris (SAP). The frequency of calcium deposits within an arc of less than 90 degrees for all calcium deposits was significantly different in culprit lesions of patients with AMI, UAP, and SAP (P<0.0001). Moreover, the average number of calcium deposits within an arc of <90 degrees per patient was significantly higher in AMI than in SAP (P<0.0005; mean+/-SD, AMI 1.4+/-1.3, SAP 0.5+/-0.8). Conversely, calcium deposits were significantly longer in SAP patients (P<0.0001; mean+/-SD, AMI 2.2+/-1.6, UAP 1.9+/-1.8, and SAP 4.3+/-3.2 mm). In AMI patients, the typical pattern was spotty calcification, associated with a fibrofatty plaque and positive remodeling. In ACS patients showing negative remodeling, no calcification was the most frequent observation. Conversely, SAP patients had the highest frequency of extensive calcification. CONCLUSIONS: Our observations show that IVUS allows the identification of vulnerable plaques in coronary arteries, not only by identifying a fibrofatty plaque and positive remodeling, but also by identifying a spotty pattern of calcification.

Aged↗

PubMed2004

Tbx1 regulates fibroblast growth factors in the anterior heart field through a reinforcing autoregulatory loop involving forkhead transcription factors.

Birth defects, which occur in one out of 20 live births, often affect multiple organs that have common developmental origins. Human and mouse studies indicate that haploinsufficiency of the transcription factor TBX1 disrupts pharyngeal arch development, resulting in the cardiac and craniofacial features associated with microdeletion of 22q11 (del22q11), the most frequent human deletion syndrome. Here, we have generated an allelic series of Tbx1 deficiency that reveals a lower critical threshold for Tbx1 activity in the cardiac outflow tract compared with other pharyngeal arch derivatives, including the palatal bones. Mice hypomorphic for Tbx1 failed to activate expression of the forkhead transcription factor Foxa2 in the pharyngeal mesoderm, which contains cardiac outflow precursors derived from the anterior heart field. We identified a Fox-binding site upstream of Tbx1 that interacted with Foxa2 and was necessary for pharyngeal mesoderm expression of Tbx1, revealing an autoregulatory loop that may explain the increased cardiac sensitivity to Tbx1 dose. Downstream of Tbx1, we found a fibroblast growth factor 8 (Fgf8) enhancer that was dependent on Tbx1 in vivo for regulating expression in the cardiac outflow tract, but not in pharyngeal arches. Consistent with its role in regulating cardiac outflow tract cells Tbx1 gain of function resulted in expansion of the cardiac outflow tract segment derived from the anterior heart field as marked by Fgf10. These findings reveal a Tbx1-dependent transcriptional and signaling network in the cardiac outflow tract that renders mouse cardiovascular development more susceptible than craniofacial development to a reduction in Tbx1 dose, similar to humans with del22q11.

Alleles↗

PubMed2004

Accuracy of measurement of left ventricular volume and ejection fraction by new real-time three-dimensional echocardiography in patients with wall motion abnormalities secondary to myocardial infarction.

Three-dimensional echocardiography is an ideal tool for the measurement of left ventricular (LV) volume because no geometric assumptions about LV shape are needed. The introduction of new real-time 3-dimensional echocardiography (RT3DE) has allowed rapid acquisition of a 3-dimensional dataset with good image quality. The purpose of this study was to examine the accuracy of RT3DE for the measurement of LV volume and ejection fraction in patients with wall motion abnormalities by using quantitative gated single-photon emission computed tomography (QGSPECT) as a reference standard. The study population consisted of 25 consecutive patients with wall motion abnormalities who underwent LV volume measurement by 2-dimensional echocardiography and by QGSPECT. LV volume and ejection fraction by RT3DE were measured offline by using the average rotation method. In 23 of 25 patients (92%), it was possible to measure 3-dimensional volume with RT3DE. RT3DE correlated well with QGSPECT in the measurement of end-diastolic volume and end-systolic volume (r = 0.97, mean difference 3.4 ml; r = 0.98, mean difference 2.0 ml, respectively), 2-dimensional echocardiography also correlated with QGSPECT but underestimated LV volume (r = 0.98, mean difference 21.1 ml; r = 0.98, mean difference 15.6 ml, respectively). Ejection fraction obtained by RT3DE had better agreement with that obtained by QGSPECT than that obtained by 2-dimensional echocardiography (r = 0.92, mean difference -0.2%; r = 0.89, mean difference -2.7%, respectively). RT3DE allows convenient and accurate estimation of LV volume and ejection fraction in patients with wall motion abnormalities.

Adult↗

PubMed2004

Detecting viable myocardium and predicting functional improvement: comparisons of positron emission tomography, rest-redistribution thallium-201 single-photon emission computed tomography (SPECT), exercise thallium-201 reinjection SPECT, I-123 BMIPP SPECT and dobutamine stress echocardiography.

BACKGROUND: Low-dose dobutamine stress echocardiography (LDDE) has become a useful and safe method for identifying hibernating or stunned myocardium and for predicting improvement in wall motion after coronary revascularization. METHODS AND RESULTS: In the present study, fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET), rest-redistribution thallium-201 ((201)Tl) single-photon emission computed tomography (RR-Tl SPECT), (123)I-15-(p-iodophenyl)-3-(R,S)-methyl pentadecanoic acid (BMIPP) and LDDE were performed in 30 patients with acute myocardial infarction (AMI) at 10+/-3 days after the onset of AMI. Also, exercise (201)Tl reinjection SPECT (RI-Tl SPECT) was performed at 14+/-2 days. Follow-up echocardiography was performed 5+/-3 months later in all patients after interventional therapy for the assessment of functional recovery. Of the 390 segments analyzed by echocardiography, 110 (28%) had abnormal wall motion. There were no significant differences between RR-Tl SPECT and LDDE in sensitivity, specificity, positive predictive value and negative predictive value using the chi(2)-test; however, in akinetic segments, there was a significant difference in sensitivity. Among FDG-PET, RI-Tl SPECT, BMIPP and LDDE, there were significant differences in 3 variables. In akinetic segments, LDDE is superior to RR-Tl SPECT in sensitivity and to FDG-PET in specificity. In hypokinetic segments, LDDE is superior to RI-Tl SPECT and BMIPP in sensitivity, and to FDG-PET and BMIPP in specificity. CONCLUSIONS: LDDE could detect functional recovery of viable myocardium in the early period of AMI and can be performed easily and safely.

Aged↗

PubMed2004

New noninvasive diagnosis of myocardial ischemia of the left circumflex coronary artery using coronary flow reserve measurement by transthoracic Doppler echocardiography: comparison with thallium-201 single photon emission computed tomography.

OBJECTIVES: The usefulness of coronary flow reserve measurement in the left circumflex coronary artery by transthoracic Doppler echocardiography to detect myocardial ischemia was compared with exercise thallium-201 single photon emission computed tomography (SPECT). METHODS: Transthoracic Doppler echocardiography was performed in 110 patients with suspected coronary artery disease. Color Doppler signals of the left circumflex coronary artery flow in the apical four-chamber view were identified, and the velocities at rest and during hyperemia recorded for calculation of coronary flow reserve by the pulsed Doppler method. All patients underwent SPECT within 1 week of the transthoracic Doppler echocardiographic study. RESULTS: Coronary flow reserve in the left circumflex coronary artery was measured in 79 (72%) of 110 patients. SPECT revealed reversible perfusion defect in the left circumflex coronary artery territories in 12 of 69 patients excluding those with multivessel disease. Coronary flow reserve < 2.0 had a sensitivity of 92% and specificity of 96% for reversible perfusion defect detected by SPECT. CONCLUSIONS: Noninvasive coronary flow reserve measurement in the left circumflex coronary artery by transthoracic Doppler echocardiography can estimate myocardial ischemia in the left ventricular lateral regions.

Aged↗

PubMed2003

Functional attenuation of UFD1l, a 22q11.2 deletion syndrome candidate gene, leads to cardiac outflow septation defects in chicken embryos.

Microdeletion of chromosome 22q11.2 is commonly associated with congenital cardiovascular defects that involve development of cranial neural crest cells (NCC) that emigrate through the pharyngeal arches. UFD1l is one of several candidate genes for 22q11.2 deletion syndrome (22q11DS). UFD1l encodes a protein whose yeast counterpart is involved in a ubiquitin-dependent proteolytic degradation pathway; however, the role of UFD1L in NCC development remains unknown. Mouse embryos that lack Ufd1l die before organogenesis. We have therefore studied the function of Ufd1l in the chick system. Chick Ufd1l encoded a 307-amino acid protein that was highly conserved with mouse and human UFD1L. Chick Ufd1l was expressed in the developing neural tube, NCC, and mesenchyme of the head and pharyngeal arch structures, as well as in the conotruncal region (cardiac outflow tract), consistent with the clinical features of 22q11DS. To determine loss-of-function effects of chick Ufd1l in NCC, we infected cardiac NCC with a retrovirus expressing antisense Ufd1l transcripts in chick embryos before their migration. Morphologic analysis of infected embryos at a later developmental stage demonstrated that functional attenuation of chick Ufd1l in cardiac NCC resulted in an increased incidence of conotruncal septation defects. These data suggest that Ufd1l may play a role in cardiac NCC during conotruncal septation.

Adaptor Proteins, Vesicular Transport↗

PubMed2003

Tbx1 is regulated by tissue-specific forkhead proteins through a common Sonic hedgehog-responsive enhancer.

Haploinsufficiency of Tbx1 is likely a major determinant of cardiac and craniofacial birth defects associated with DiGeorge syndrome. Although mice deficient in Tbx1 exhibit pharyngeal and aortic arch defects, the developmental program and mechanisms through which Tbx1 functions are relatively unknown. We identified a single cis-element upstream of Tbx1 that recognized winged helix/forkhead box (Fox)-containing transcription factors and was essential for regulation of Tbx1 transcription in the pharyngeal endoderm and head mesenchyme. The Tbx1 regulatory region was responsive to signaling by Sonic hedgehog (Shh) in vivo. We show that Shh is necessary for aortic arch development, similar to Tbx1, and is also required for expression of Foxa2 and Foxc2 in the pharyngeal endoderm and head mesenchyme, respectively. Foxa2, Foxc1, or Foxc2 could bind and activate transcription through the critical cis-element upstream of Tbx1, and Foxc proteins were required, within their expression domains, for Tbx1 transcription in vivo. We propose that Tbx1 is a direct transcriptional target of Fox proteins and that Fox proteins may serve an intermediary role in Shh regulation of Tbx1.

Animals↗

PubMed2003

Unraveling the genetic and developmental mysteries of 22q11 deletion syndrome.

Birth defects occur in nearly 5% of all live births and are the major cause of infant mortality and morbidity. Despite the recent progress in molecular and developmental biology, the underlying genetic etiology of most congenital anomalies remains unknown. Heterozygous deletion of the 22q11.2 locus results in the most common human genetic deletion syndrome, known as DiGeorge syndrome, and has served as an entry to understanding the basis for numerous congenital heart and craniofacial anomalies, among many other defects. Extensive human genetic analyses, mouse modeling and studies of developmental molecular cascades involved in 22q11 deletion syndrome are revealing complex networks of signaling and transcriptional events that are essential for normal embryonic development. Armed with this knowledge, we can now begin to consider the multiple genetic "hits" that might contribute to developmental anomalies, some of which could provide targets for in utero prevention of birth defects.

Animals↗