scholarly journals Gene-teratogen interactions influence the penetrance of birth defects by altering Hedgehog signaling strength

Development ◽  
2021 ◽  
Vol 148 (19) ◽  
Author(s):  
Jennifer H. Kong ◽  
Cullen B. Young ◽  
Ganesh V. Pusapati ◽  
F. Hernán Espinoza ◽  
Chandni B. Patel ◽  
...  
Keyword(s):  
Small Molecules ◽  
Birth Defects ◽  
Birth Defect ◽  
Hedgehog Signaling ◽  
Multiple Birth ◽  
In Utero Exposure ◽  
Membrane Protein Complex ◽  
Protein Target ◽  
Hh Signaling ◽  
Genetic And Environmental Factors

ABSTRACT Birth defects result from interactions between genetic and environmental factors, but the mechanisms remain poorly understood. We find that mutations and teratogens interact in predictable ways to cause birth defects by changing target cell sensitivity to Hedgehog (Hh) ligands. These interactions converge on a membrane protein complex, the MMM complex, that promotes degradation of the Hh transducer Smoothened (SMO). Deficiency of the MMM component MOSMO results in elevated SMO and increased Hh signaling, causing multiple birth defects. In utero exposure to a teratogen that directly inhibits SMO reduces the penetrance and expressivity of birth defects in Mosmo−/− embryos. Additionally, tissues that develop normally in Mosmo−/− embryos are refractory to the teratogen. Thus, changes in the abundance of the protein target of a teratogen can change birth defect outcomes by quantitative shifts in Hh signaling. Consequently, small molecules that re-calibrate signaling strength could be harnessed to rescue structural birth defects.

scholarly journals Gene-teratogen interactions influence the penetrance of birth defects by altering Hedgehog signaling strength

2021 ◽  
Author(s):  
Jennifer Kong ◽  
Cullen B Young ◽  
Ganesh Pusapati ◽  
F Hernan Espinoza ◽  
Chandni Patel ◽  
...  
Keyword(s):  
Small Molecules ◽  
Birth Defects ◽  
Birth Defect ◽  
Hedgehog Signaling ◽  
Multiple Birth ◽  
In Utero Exposure ◽  
Membrane Protein Complex ◽  
Protein Target ◽  
Hh Signaling ◽  
Genetic And Environmental Factors

Birth defects result from interactions between genetic and environmental factors, but the mechanisms remain poorly understood. We find that mutations and teratogens interact in predictable ways to cause birth defects by changing target cell sensitivity to Hedgehog (Hh) ligands. These interactions converge on a membrane protein complex, the MMM complex, that promotes degradation of the Hh transducer Smoothened (SMO). Deficiency of the MMM component MOSMO results in elevated SMO and increased Hh signaling, causing multiple birth defects. In utero exposure to a teratogen that directly inhibits SMO reduces the penetrance and expressivity of birth defects in Mosmo-/- embryos. Additionally, tissues that develop normally in Mosmo-/- embryos are refractory to the teratogen. Thus, changes in the abundance of the protein target of a teratogen can change birth defect outcomes by quantitative shifts in Hh signaling. Consequently, small molecules that re-calibrate signaling strength could be harnessed to rescue structural birth defects.

scholarly journals Regulation of Hedgehog Signaling by miRNAs and Nanoformulations: A Possible Therapeutic Solution for Colorectal Cancer

2021 ◽  
Vol 10 ◽  
Author(s):  
Zeeshan Javed ◽  
Muhammad Javed Iqbal ◽  
Amna Rasheed ◽  
Haleema Sadia ◽  
Shahid Raza ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Small Molecules ◽  
Hedgehog Signaling ◽  
Target Genes ◽  
Therapeutic Option ◽  
High Specificity ◽  
Alternative Drug ◽  
Delivery Platform ◽  
Hh Signaling ◽  
Differentiation And Proliferation

Hedgehog (Hh) signaling aberrations trigger differentiation and proliferation in colorectal cancer (CRC). However, the current approaches which inhibit this vital cellular pathway provoke some side effects. Therefore, it is necessary to look for new therapeutic options. MicroRNAs are small molecules that modulate expression of the target genes and can be utilized as a potential therapeutic option for CRC. On the other hand, nanoformulations have been implemented in the treatment of plethora of diseases. Owing to their excessive bioavailability, limited cytotoxicity and high specificity, nanoparticles may be considered as an alternative drug delivery platform for the Hh signaling mediated CRC. This article reviews the Hh signaling and its involvement in CRC with focus on miRNAs, nanoformulations as potential diagnostic/prognostic and therapeutics for CRC.

scholarly journals Mechanisms of Smoothened Regulation in Hedgehog Signaling

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 2138
Author(s):  
Jie Zhang ◽  
Zulong Liu ◽  
Jianhang Jia
Keyword(s):  
Small Molecules ◽  
Intracellular Trafficking ◽  
Hedgehog Signaling ◽  
Transmembrane Protein ◽  
Developmental Defects ◽  
Hh Signaling ◽  
Development Outcomes ◽  
Late Stages ◽  
Signaling Activity

The seven-transmembrane protein, Smoothened (SMO), has shown to be critical for the hedgehog (HH) signal transduction on the cell membrane (and the cilium in vertebrates). SMO is subjected to multiple types of post-translational regulations, including phosphorylation, ubiquitination, and sumoylation, which alter SMO intracellular trafficking and cell surface accumulation. Recently, SMO is also shown to be regulated by small molecules, such as oxysterol, cholesterol, and phospholipid. The activity of SMO must be very well balanced by these different mechanisms in vivo because the malfunction of SMO will not only cause developmental defects in early stages, but also induce cancers in late stages. Here, we discuss the activation and inactivation of SMO by different mechanisms to better understand how SMO is regulated by the graded HH signaling activity that eventually governs distinct development outcomes.

scholarly journals Periconceptional folic acid intake in Northwest Russia: a birth registry study

2020 ◽  
Vol 30 (Supplement_5) ◽  
Author(s):  
V A Postoev ◽  
L I Menshikova ◽  
A A Usynina ◽  
A M Grjibovski ◽  
J O Odland
Keyword(s):  
Folic Acid ◽  
Birth Defects ◽  
Birth Defect ◽  
Demographic Factors ◽  
Folic Acid Supplementation ◽  
Demographic Characteristics ◽  
Prenatal Counseling ◽  
Folic Acid Intake ◽  
Birth Registry ◽  
Socio Demographic Factors

Abstract Introduction Periconceptional use of folic acid supplementation is an evidence-based measure of birth defects prevention. The study was aimed to assess effect of periconceptual use of folic acid on birth defect prevalence in Arkhangelsk county and to investigate socio-demographic factors, which are associated with adherence to this preventive measure. Methods A registry-based study was conducted with data from the Arkhangelsk County Birth Registry for 2012-2015. The study population included 57084 pregnancies to calculate the proportion of women taking folic acid and 53340 pregnancy outcomes without missing data to analyze related socio-demographic characteristics. Results The proportion of women followed a folic acid supplementation before pregnancy was 1.3% (95% CI: 1.2-1.4), during pregnancy - 55.8% (95%CI: 54.6-56.4). Such women had less risk to deliver a newborn with any birth defects (OR = 0,84, 95%CI: 0,75 - 0,95). Considering birth defects prevalence of 38,6 per 1000 newborns in Arkhangelsk county, number needed to prevent one case of birth defect was 142,9. Based on multivariate analysis, nulliparous married women with higher education, aged 30 or more, had a higher chance to use folic acid before and during pregnancy. The history of spontaneous abortion in the mother's medical history and the first pregnancy were negatively associated with the probability of folic acid intake both before and during pregnancy. Conclusions The compliance to periconceptional intake of folic acid among women in the region was low. A level of compliance was associated with such socio-demographic factors as age, education, marital status, gravidity and parity. The findings have direct applications in improving prenatal care in Arkhangelsk county and establishing targets for prenatal counseling. Key messages A level of compliance to primary prevention of birth defects is associated with such socio-demographic factors as age, education, marital status, gravidity and parity. Prenatal counseling in terms of birth defects prevention should be based on socio-demographic characteristics of pregnant women.

Pregnancy Experience after Delivery of a Child with a Major Birth Defect: A Population Study

PEDIATRICS ◽  
1995 ◽  
Vol 95 (1) ◽  
pp. 59-65
Author(s):  
Margarett K. Davis ◽  
Muin J. Khoury ◽  
J. David Erickson
Keyword(s):  
Birth Defects ◽  
Reproductive Behavior ◽  
Birth Defect ◽  
Large Population ◽  
Population Based ◽  
Subsequent Pregnancy ◽  
Pregnancy Rates ◽  
Wide Range ◽  
First Year Of Life ◽  
And Control

Objective. Data from a large population-based, case-control study were analyzed to determine whether women giving birth to children with major birth defects have different subsequent pregnancy patterns than those giving birth to live-born babies without defects. Other studies examining this phenomenon have been smaller, have not been population-based, or have not addressed the different effects that a wide range of major defects might have on mothers' subsequent pregnancy rates. Methods. Mothers of 4918 infants with major birth defects born from 1968 through 1980 in metropolitan Atlanta were compared with mothers of 3029 control infants, frequency-matched on birth year, birth hospital, and race. Results. The pregnancy rate in the first 3 years after the index birth was higher among case mothers (36%) than among control mothers (30%, P < .0001). This excess was seen for mothers of stillborn case infants (64%) and mothers of case infants who died in infancy (58%), but not for mothers of case infants who survived the first year of life (31%). Pregnancy rates varied by birth defect type. Maternal and infant factors varied among case and control subjects and influenced subsequent pregnancy rates. Conclusion. The reproductive behavior observed in this study supports the theory that mothers of nonsurviving children with birth defects compensate by acting to "replace" the lost child. Reproductive behavior was also strongly associated with having completed a previous pregnancy and by the type of birth defect.

scholarly journals Burden and consequence of birth defects in Nepal-evidence from prospective cohort study

2021 ◽  
Author(s):  
Prajwal Paudel ◽  
Avinash K Sunny ◽  
Rejina Gurung ◽  
Abhishek Gurung ◽  
Honey Malla ◽  
...  
Keyword(s):  
Risk Factor ◽  
Cohort Study ◽  
Prospective Cohort Study ◽  
Birth Defects ◽  
Prospective Cohort ◽  
Birth Defect ◽  
Cleft Lip ◽  
Cleft Lip And Palate ◽  
Birth Asphyxia ◽  
Neonatal Infection

Abstract Background-Every year an estimated 7.9 million babies are born with birth defect. Of these babies, more than 3 million die and 3.2 million have disability. Improving nationwide information on prevalence of birth defect, risk factor and consequence is required for better resource allocation for prevention, management and rehabilitation. In this study, we assess the prevalence of birth defect, associated risk factors and consequences in Nepal.Method-This is a prospective cohort study conducted in 12 hospitals of Nepal for 18 months. All the women who delivered in the hospitals during the study period was enrolled. Independent researchers collected data on the social and demographic information using semi-structured questionnaire at the time of discharge and clinical events and birth outcome information from the clinical case note. Data were analyzed on the prevalence and type of birth defect. Logistic regression was done to assess the risk factor and consequences for birth defect. Results-Among the total 87,242 livebirths, the prevalence of birth defects was found to be 5.8 per 1000 live births. The commonly occurring birth defects were anencephaly (3.95%), cleft lip (2.77%), cleft lip and palate (6.13%), clubfeet (3.95%), eye abnormalities (3.95%) and meningomyelocele (3.36%). The odds of birth defect was higher among mothers with age <20 years (adjusted Odds ratio (aOR) 1.64; 95% CI, 1.18-2.28) and disadvantaged ethnicity (aOR 1.78; 95% CI, 1.46-2.18). The odds of birth asphyxia was twice fold higher among babies with birth defect (aOR 1.88; 95% CI, 1.41-2.51) in reference with babies without birth defect. The odds of neonatal infection was twice fold higher among babies with birth defect (aOR 1.82; 95% CI, 1.12-2.96) in reference with babies without birth defect. Babies with birth defect had three-fold risk of pre-discharge mortality (aOR 3.00; 95% CI, 1.93-4.69). Conclusion- Babies with birth defect have high risk for birth asphyxia, neonatal infection and pre-discharge mortality at birth. Further evaluation on the care provided to babies who have birth defect is warranted.

scholarly journals Demographic Characteristics of Mothers Who Delivered Children with Birth Defetcs

2018 ◽  
pp. 222-227
Author(s):  
Yudianto B Saroyo ◽  
Christian Wijaya ◽  
Putri M T Marsubin
Keyword(s):  
Retrospective Study ◽  
Birth Weight ◽  
Antenatal Care ◽  
Birth Defects ◽  
Medical Records ◽  
Birth Defect ◽  
Demographic Characteristics ◽  
Comorbid Disease ◽  
Increased Risk

Abstract Objective: to determine the characteristics and background of mothers who delivered neonates with birth defects. Methods: A retrospective study was used by evaluating the medical records of patients with birth defects in Dr. Cipto Mangunkusumo Hospital during the period between September 2014 and June 2016. Results: A total of 67 (1.85%) out of 3,619 infants who were born in Dr. Cipto Mangunkusumo Hospital during the period between September 2014 and June 2016 had birth defects. Forty-seven (70.1%) mothers of the subjects irregularly attend antenatal care. The most frequent maternal comorbid disease in this study was asthma, which was found in 4 (5.97%) mothers of the subjects. 48 (58.7%) subjects had birth weight under 2500 g. Conclusion: In this retrospective study, the main highlight is that 70.1% of the mothers who delivered neonates with birth defects did not attend antenatal care regularly. 58.7% of the neonates with birth defects had low birth weight. This study could be used as base for further research investigating about the role of antenatal care in early detection and/or the planning of delivery for babies with birth defects. Trends in babies with birth defects suggested that fetuses diagnosed with IUGR/SGA should be given special attention, as they were at increased risk for birth defects. Keywords: birth defect, maternal description   Abstrak Tujuan: untuk mengetahui deskripsi/ciri-ciri  dan latar belakang ibu yang melahirkan janin dengan kelainan bawaan. Metode: Studi retrospektif digunakan dengan menggunakan data sekunder rekam medis pasien dengan kelainan bawaan di Rumah Sakit Umum Pusat Nasional Dr. Cipto Mangunkusumo pada periode September 2014-Juni 2016. Hasil: Sejumlah 67 (1.85%) dari 3,619 neonatus didapatkan dengan kelainan bawaan di RSUPN Cipto Mangunkusumo pada periode September 2014-Juni 2016 . Sejumlah 47 (70.1%) ibu dari subjek tidak teratur dalam melakukan kunjungan antenatal care. Penyakit komorbid ibu yang paling banyak ditemukan dalam studi ini adalah asma, yang ditemukan dalam 4 (5.97%) subjek. 48 (58.7%) subyek memiliki berat lahir di bawah 2500 g. Kesimpulan: Pada studi retrospektif ini didapatkan 70.1% ibu yang melahirkan bayi dengan kelainan bawaan tidak melakukan kunjungan antenatal care. Didapatkan bahwa 58,7% bayi yang lahir dengan kelainan bawaan memiliki berat badan lahir rendah (BBLR). Studi ini dapat dijadikan sebagai landasan dilakukannya studi yang lebih besar untuk mengevaluasi peran antenatal care terhadap deteksi dini dan/atau perencanaan persalinan bayi dengan kelainan bawaan. Tren pada bayi dengan kelainan bawaan menunjukkan bahwa janin yang pada antenatal care didapatkan IUGR/SGA patut diperhatikan lebih untuk kecurigaan kemungkinan adanya kelainan bawaan. Kata kunci:   deskripsi ibu,   kelainan bawaan,

scholarly journals Osteocalcin expressing cells from tendon sheaths in mice contribute to tendon repair by activating Hedgehog signaling

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Yi Wang ◽  
Xu Zhang ◽  
Huihui Huang ◽  
Yin Xia ◽  
YiFei Yao ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Hedgehog Signaling ◽  
Progenitor Cell ◽  
Tendon Repair ◽  
Tendon Sheath ◽  
Lineage Tracing ◽  
Specific Marker ◽  
Molecular Function ◽  
Hh Signaling ◽  
Necessary And Sufficient

Both extrinsic and intrinsic tissues contribute to tendon repair, but the origin and molecular functions of extrinsic tissues in tendon repair are not fully understood. Here we show that tendon sheath cells harbor stem/progenitor cell properties and contribute to tendon repair by activating Hedgehog signaling. We found that Osteocalcin (Bglap) can be used as an adult tendon-sheath-specific marker in mice. Lineage tracing experiments show that Bglap-expressing cells in adult sheath tissues possess clonogenic and multipotent properties comparable to those of stem/progenitor cells isolated from tendon fibers. Transplantation of sheath tissues improves tendon repair. Mechanistically, Hh signaling in sheath tissues is necessary and sufficient to promote the proliferation of Mkx-expressing cells in sheath tissues, and its action is mediated through TGFβ/Smad3 signaling. Furthermore, co-localization of GLI1+ and MKX+ cells is also found in human tendinopathy specimens. Our work reveals the molecular function of Hh signaling in extrinsic sheath tissues for tendon repair.

Role of knot (kn) in Wing Patterning in Drosophila

Genetics ◽  
1997 ◽  
Vol 147 (3) ◽  
pp. 1203-1212 ◽  
Author(s):  
Katerina Nestoras ◽  
Helena Lee ◽  
Jym Mohler
Keyword(s):  
Hedgehog Signaling ◽  
Imaginal Disc ◽  
Hedgehog Signaling Pathway ◽  
Posterior Compartment ◽  
Drosophila Wing ◽  
Compartment Boundary ◽  
Hh Signaling ◽  
Embryonic Segmentation ◽  
Anterior Posterior

We have undertaken a genetic analysis of new strong alleles of knot (kn). The original kn1 mutation causes an alteration of wing patterning similar to that associated with mutations of fused (fu), an apparent fusion of veins 3 and 4 in the wing. However, unlike fu, strong kn mutations do not affect embryonic segmentation and indicate that kn is not a component of a general Hh (Hedgehog)-signaling pathway. Instead we find that kn has a specific role in those cells of the wing imaginal disc that are subject to ptc-mediated Hh-signaling. Our results suggest a model for patterning the medial portion of the Drosophila wing, whereby the separation of veins 3 and 4 is maintained by kn activation in the intervening region in response to Hh-signaling across the adjacent anterior-posterior compartment boundary.

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