Folic acid and homocysteine affect neural crest and neuroepithelial cell outgrowth and differentiation in vitro

Boot, Marit J.; Steegers‐Theunissen, R.P.M.; Poelmann, Robert E.; Iperen, Liesbeth van; Lindemans, Jan; Groot, Adriana C. Gittenberger‐de

doi:10.1002/dvdy.10303

Cited by 98 publications

(70 citation statements)

References 47 publications

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“…In the chick embryo, we found elevated Hcys inhibits the entry of newly-formed cardiac NC cells (NC cells derived from the mid-otic to third somite axial levels) into the S-phase of the cell cycle, decreases cardiac NC cell number, and decreases the distance that cardiac NC cells migrate from the neural tube in vivo (Tierney et al, 2004). In addition, elevated Hcys alters cardiac NC cell migratory behavior, cell shape, and differentiation in vitro (Brauer and Rosenquist, 2002;Boot et al, 2003). In cultured mouse cardiac NC cells, elevated Hcys increases connexin-43 expression and increases connexin-43 localization with NC cell processes (Boot et al, 2006).…”

Section: Introductionmentioning

confidence: 97%

Homocysteine enhances cardiac neural crest cell attachment in vitro by increasing intracellular calcium levels

Heidenreich

Reedy

Brauer

2008

Developmental Dynamics

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Elevated homocysteine (Hcys) increases the risk of neurocristopathies. Previous studies show Hcys inhibits neural crest (NC) cell migration in vivo. However, the mechanisms responsible for this effect are unknown. Here, we evaluated the effect of Hcys on NC cell attachment in vitro and determined if any of the effects were due to altered Ca 2؉ signaling. We found Hcys enhanced NC cell attachment in a dose and substratedependent manner. Ionomycin mimicked the effect of Hcys while BAPTA-AM and 2-APB blocked the effect of Hcys on NC attachment. In contrast, inhibitors of plasma membrane Ca 2؉ channels had no effect on NC attachment. Hcys also increased the emission of the intracellular Ca 2؉ -sensitive probe, Fluo-4. These results show Hcys alters NC attachment by triggering an increase in intracellular Ca 2؉ possibly by generating inositol triphosphate. Hence, the teratogenic effect ascribed to Hcys may be due to perturbation of intracellular Ca 2؉ signaling.

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Section: Introductionmentioning

confidence: 97%

Homocysteine enhances cardiac neural crest cell attachment in vitro by increasing intracellular calcium levels

Heidenreich

Reedy

Brauer

2008

Developmental Dynamics

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“…Folic Acid, DNA Methylation, and NTDs It has been known for sometime that folic acid deficiency contributes to NTDs but the mechanism currently remains vague (Bohnsack and Hirschi, 2004;Boot et al, 2003;Finnell et al, 2002;Johnson et al, 1999;Rosenquist et al, 1996;Whitehead et al, 1995). Folate deficiency occurs in about 10% of the US population and low folic acid has been associated with chromosomal damage, including strand breaks and misincorporation of uracil into DNA (Blount et al, 1997;Duthie and Hawdon, 1998;Pogribny et al, 2006b).…”

Section: Understanding the Causes Of Ntdsmentioning

confidence: 99%

“…The precursor cells for both neural crest cells and the neuroepithelial cells of the neural tube also have a higher level of folate receptor expression (Boot et al, 2003). Research has shown that folic acid levels directly correlate to genomic DNA methylation and deficiency is associated with global genomic hypomethylation, which is reversible with repletion therapy (Bohnsack and Hirschi, 2004;Choi et al, 2005;Pufulete et al, 2005;Rampersaud et al, 2000).…”

Section: Understanding the Causes Of Ntdsmentioning

confidence: 99%

A new perspective on neural tube defects: Folic acid and microRNA misexpression

Shookhoff

Gallicano

2010

Genesis

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Summary: Neural tube defects (NTDs) are the second most common birth defects in the United States. It is well known that folic acid supplementation decreases about 70% of all NTDs, although the mechanism by which this occurs is still relatively unknown. The current theory is that folic acid deficiency ultimately leads to depletion of the methyl pool, leaving critical genes unmethylated, and, in turn, their improper expression leads to failure of normal neural tube development. Recently, new studies in human cell lines have shown that folic acid deficiency and DNA hypomethylation can lead to misexpression of microRNAs (miRNAs). Misexpression of critical miRNAs during neural development may lead to a subtle effect on neural gene regulation, causing the sometimes mild to severely debilitating range of phenotypes exhibited in NTDs. This review seeks to cohesively integrate current information regarding folic acid deficiency, methylation cycles, neural development, and miRNAs to propose a potential model of NTD formation. In addition, we have examined the relevant gene pathways and miRNAs that are predicted to affect them, and based on our investigation, we have devised a basic template of experiments for exploring the idea that miRNA misregulation may be linked to folic acid deficiency and NTDs. genesis 48:282-294, 2010. V V C 2010 Wiley-Liss, Inc.

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“…Furthermore, abnormal folate metabolism that results from the methylenetetrahydrofolate reductase 677C>T mutation produces a significantly increased risk for conotruncal but not other heart defects (van Beynum et al, 2006). We (Rosenquist et al, 1996;Brauer and Rosenquist, 2002) and others (Boot et al, 2003(Boot et al, , 2004 have shown that the hyperhomocysteinemia that accompanies low folate or abnormal folate metabolism impairs the development of the cardiac neural crest, resulting in abnormal development of the conotruncal region of the heart.…”

Section: Introductionmentioning

confidence: 96%

“…These kinds of defects are the most common developmental defects of the cardiovascular system that are observed in the human population, and may include ventricular septal defects, persistent truncus arteriosus, transposition of the great arteries, double outlet right ventricle, tetralogy of Fallot, interrupted aortic arch, and pulmonary atresia (e.g., Kirby et al, 1983;Cavieres and Smith, 2000;Nishijima et al, 2000;Boot et al, 2003Boot et al, , 2004Rosenquist et al, 2007;Varadkar et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

High‐affinity folate receptor in cardiac neural crest migration: A gene knockdown model using siRNA

Rosenquist

Chaudoin

Finnell

et al. 2010

Developmental Dynamics

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Folate supplementation reduces the incidence of congenital heart defects, but the nature of this protective mechanism remains unclear. Immunolabeling demonstrated that the neural tube and neural crest (NC) cells were rich in the high-affinity folate receptor FOLR1and during the early stages of development FOLR1 was found principally in these cells. Suppression of Folr1 expression in the nascent cardiac NC by site-directed short-interfering RNA (siRNA) altered cardiac NC cell mitosis and subsequent migration patterns leading to abnormal development of the pharyngeal arch arteries (PAA) and outflow tract. qPCR analysis demonstrated that the siRNA treatment significantly reduced Folr1 24 hr after treatment. These treatments also significantly reduced mitosis in the neural tube, but adjacent, nontreated areas were unaffected. In summary, a brief reduction in the expression of Folr1 during a critical stage of NC development had long-term consequences for the development of the PAA and outflow tract. Developmental Dynamics 239:1136-1144,

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Folic acid and homocysteine affect neural crest and neuroepithelial cell outgrowth and differentiation in vitro

Abstract: The beneficial effect of additional folic acid in the periconceptional period to prevent neural tube defects, orofacial clefts, and conotruncal heart defects in the offspring has been shown.

Cited by 98 publications

References 47 publications

Homocysteine enhances cardiac neural crest cell attachment in vitro by increasing intracellular calcium levels

Homocysteine enhances cardiac neural crest cell attachment in vitro by increasing intracellular calcium levels

A new perspective on neural tube defects: Folic acid and microRNA misexpression

High‐affinity folate receptor in cardiac neural crest migration: A gene knockdown model using siRNA

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