Retinoic acid regulates programmed cell death through BMP signalling

10.1038/10098 ◽  
1999 ◽  
Vol 1 (2) ◽  
pp. 125-126 ◽  
Author(s):  
J. Rodriguez-Leon ◽  
R. Merino ◽  
D. Macias ◽  
Y. Gañan ◽  
E. Santesteban ◽  
...  
Keyword(s):  
Cell Death ◽  
Retinoic Acid ◽  
Programmed Cell Death ◽  
Bmp Signalling

Retinoic acid alters EGF receptor expression during palatogenesis

Development ◽  
1988 ◽  
Vol 102 (4) ◽  
pp. 853-867 ◽  
Author(s):  
B.D. Abbott ◽  
E.D. Adamson ◽  
R.M. Pratt
Keyword(s):  
Cell Death ◽  
Retinoic Acid ◽  
Epithelial Cells ◽  
Programmed Cell Death ◽  
Egf Receptor ◽  
Receptor Expression ◽  
Egf Receptors ◽  
Receptor Localization ◽  
All Trans Retinoic Acid ◽  
Fetal Mice

Various growth factors are necessary for normal embryonic development and EGF receptors are present in developing palatal shelves of embryonic/fetal mice at least from day 12 of gestation. The medial epithelium of the palatal shelf undergoes a series of developmental events which do not occur in the oral and nasal epithelia. In utero and in organ culture, the control palatal medial epithelium shows a developmental decline in EGF receptors, demonstrated both by a decrease in the binding of antibody to EGF receptors and a decrease in the binding of 125I-EGF; decreases which are not observed in cells of the adjacent oral or nasal epithelium. During this period, medial cells cease DNA synthesis and undergo programmed cell death. Medial epithelial cells exposed to all-trans-retinoic acid continue to express EGF receptors, bind EGF, proliferate, fail to undergo programmed cell death and exhibit a morphology typical of nasal cells. The data suggest that this disturbance by retinoic acid of EGF receptor localization and subsequent alterations in differentiation of the epithelial cells plays a role in the retinoic-acid-mediated induction of cleft palate.

Endogenous bone morphogenetic proteins regulate outgrowth and epithelial survival during avian lip fusion

Development ◽  
2002 ◽  
Vol 129 (19) ◽  
pp. 4647-4660 ◽  
Author(s):  
Amir M. Ashique ◽  
Katherine Fu ◽  
Joy M. Richman
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Bone Morphogenetic Proteins ◽  
Loss Of Function ◽  
Rapid Induction ◽  
Similar Phenotype ◽  
Primary Palate ◽  
Bmp Signalling ◽  
Frontonasal Mass

Our expression studies of bone morphogenetic proteins (BMPs) and Noggin (a BMP antagonist) in the embryonic chicken face suggested that BMP signals were important for closure of the upper lip or primary palate. We noted that Noggin expression was restricted to the frontonasal mass epithelium but was reduced at the corners of the frontonasal mass (globular processes) just prior to fusion with the adjacent maxillary prominences. We therefore performed gain- and loss-of-function experiments to determine the role of BMPs in lip formation. Noggin treatment led to reduced proliferation and outgrowth of the frontonasal mass and maxillary prominences and ultimately to the deletion of the maxillary and palatine bones. The temporary block in BMP signalling in the mesenchyme also promoted epithelial survival. Noggin treatment also upregulated expression of endogenous BMPs, therefore we investigated whether increasing BMP levels would lead to the same phenotype. A BMP2 bead was implanted into the globular process and a similar phenotype to that produced by Noggin resulted. However, instead of a decrease in proliferation, defects were caused by increased programmed cell death, first in the epithelium and then in the mesenchyme. Programmed cell death was induced primarily in the lateral frontonasal mass with very little cell death medial to the bead. The asymmetric cell death pattern was correlated with a rapid induction of Noggin in the same embryos, with transcripts complementary to the regions with increased cell death. We have demonstrated a requirement for endogenous BMP in the proliferation of facial mesenchyme and that mesenchymal signals promote either survival or thinning of the epithelium. We furthermore demonstrated in vivo that BMP homeostasis is regulated by increasing expression of ligand or antagonist and that such mechanisms may help to protect the embryo from changes in growth factor levels during development or after exposure to teratogens.

scholarly journals Programmed Cell Death Is Required for Palate Shelf Fusion and Is Regulated by Retinoic Acid

2002 ◽  
Vol 245 (1) ◽  
pp. 145-156 ◽  
Author(s):  
Rodrigo Cuervo ◽  
Concepción Valencia ◽  
Roshantha A.S. Chandraratna ◽  
Luis Covarrubias
Keyword(s):  
Cell Death ◽  
Retinoic Acid ◽  
Programmed Cell Death

scholarly journals Teratogens and craniofacial malformations: relationships to cell death

Development ◽  
1988 ◽  
Vol 103 (Supplement) ◽  
pp. 213-232 ◽  
Author(s):  
K. K. Sulik ◽  
C. S. Cook ◽  
W. S. Webster
Keyword(s):  
Cell Death ◽  
Retinoic Acid ◽  
Programmed Cell Death ◽  
Ionizing Radiation ◽  
Acute Treatment ◽  
Cleft Lip ◽  
Neural Crest Cell ◽  
Cell Populations ◽  
Craniofacial Malformations ◽  
Facial Clefts

Environmental agents including ethanol, 13-cis retinoic acid (RA, Accutane®), the antimetabolite methotrexate, periods of hypoxia, ionizing radiation or hyperthermic stress, when administered acutely to pregnant experimental animals, induce stage-dependent craniofacial malformations comparable to those in corresponding human teratogen syndromes. Acute treatment regimens have allowed analysis of cell populations initially affected and subsequent dysmorphogenetic sequences as well as speculation relative to mechanisms of teratogenesis. In rodent models, ethanol and RA appear to affect similar cell populations and comparable malformations can be induced by both agents. When administered during gastrulation they cause a major insult to the anterior neural plate which results in characteristic ocular, brain and facial malformations comparable to those seen in the fetal alcohol syndrome. Exposure to these drugs at a time just prior to and during neural crest cell migration into the craniofacial and cervical regions results in malformations comparable to those seen in the Di-George sequence and/or retinoic acid embryopathy. Slightly later, at the time that the epibranchial placodes are active, insult results in mandibulofacial dysostosis-like syndromes. We propose that the pattern of these malformations is related to the particular vulnerability of cells in the vicinity of normal programmed cell death. Cell death is also associated with ionizing radiation and hyperthermia-induced malformations. Both of these teratogens are particularly damaging to the early development of the eye and central nervous system. Teratogenic temperature elevations result in arrest of mitotic activity and death of cells in mitosis. Hypoxia is also associated with cell death in specific regions and subsequent malformation. For example, death of cells in the invaginating olfactory placode has recently been associated with cleft lip formation. The relationship of hypoxiainduced cell death to energy requirements is being explored. Acute treatment with methotrexate results in frontonasal dysplasia (median facial clefts). Combined effects of fluid imbalance, lack of proliferation or death of frontonasal mesenchyme appear to be involved. Although the mechanisms of craniofacial malformation are complex, a common feature for many is excessive cell death for which the embryo may be unable to compensate. Excessive cell death in regions of programmed cell death represents an important, yet little appreciated, mechanism of teratogenesis.

Redox Regulation of Retinoic Acid Receptor Function in Myeloid Leukemia Cell Differentiation and Apoptosis.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2483-2483
Author(s):  
Kent A. Robertson ◽  
Meihua Luo ◽  
Ashley Chastain ◽  
Scott Colvin ◽  
April Reed ◽  
...  
Keyword(s):  
Cell Death ◽  
Retinoic Acid ◽  
Programmed Cell Death ◽  
Growth Inhibition ◽  
Myeloid Leukemia ◽  
Redox Regulation ◽  
Retinoic Acid Receptor ◽  
Leukemia Cell ◽  
Granulocytic Differentiation ◽  
Acid Receptor

Abstract Ape1/ref-1 is a multifunctional base excision DNA repair protein that is involved in the repair of abasic sites in DNA. However, it also has a distinct role in the redox regulation of a variety of cellular proteins, such as Fos, Jun, p53, NFkB, PAX, HIF-1a, HLF, and others. Ape-1/ref-1 maintains these proteins in a reduced state thereby facilitating their DNA binding and transcriptional activation capability. HL-60 cells are known to respond to retinoic acid (RA) with terminal granulocytic differentiation and apoptosis, which is mediated through the RA receptors. Previous experiments suggested that Ape1/ref-1 expression is related to apoptosis. To further define this relationship, we used retroviral gene transduction to over-express HA-tagged Ape1/ref-1 in HL-60 myeloid leukemia cells. We observed that the RA-induced growth inhibition of HL-60 cells over-expressing Ape1/ref-1 was significantly enhanced compared to wild type HL-60 cells. To determine if the growth inhibition was related to enhanced programmed cell death and differentiation, we treated Ape1/ref-1 transduced and vector-only (LXSN) transduced HL-60 cells with RA and evaluated the expression of Ape1/ref-1 and the development of apoptosis and markers of differentiation. Results: 1) RA induced expression of the retroviral Ape1/ref-1 construct as determined by Western blot resulting in a higher (ie retroviral + endogenous Ape1/ref-1) overall expression of Ape1/ref-1 compared to control cells; 2) analysis of RA-treated cells for apoptosis by propidium iodide, TUNEL, and Annexin V staining as well as morphology, unexpectedly demonstrated enhanced programmed cell death in cells expressing the transduced Ape1/ref-1; 3) Ape-1 over-expression enhanced the retinoid differentiation response by morphology and expression of CD11b. Additional mobility shift experiments demonstrated the redox dependence of retinoic acid receptor binding to retinoid response elements mediated by Ape-1/ref-1. In conclusion, our data supports the contention that Ape1/ref-1 expression may be important for mediating RA-induced myeloid differentiation and programmed cell death.

The WNT antagonist cSFRP2 modulates programmed cell death in the developing hindbrain

Development ◽  
2000 ◽  
Vol 127 (24) ◽  
pp. 5285-5295 ◽  
Author(s):  
D.L. Ellies ◽  
V. Church ◽  
P. Francis-West ◽  
A. Lumsden
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Neural Crest ◽  
Neural Crest Cells ◽  
Over Expression ◽  
Bmp4 Expression ◽  
Bmp Signalling

In the avian hindbrain, the loss of premigratory neural crest cells from rhombomeres 3 and 5 (r3, r5) through programmed cell death contributes to the patterning of emigrant crest cells into three discrete streams. Programmed cell death is induced by the upregulation of Bmp4 and Msx2 in r3 and r5. We show that cSFRP2, a WNT antagonist, is expressed in the even-numbered rhombomeres and that over-expression of cSfrp2 inhibits Bmp4 expression in r3 and r5, preventing programmed cell death. By contrast, depleting cSFRP2 function in r4 results in elevated levels of Msx2 expression and ectopic programmed cell death, as does overexpression of Wnt1. We propose that programmed cell death in the rhombencephalic neural crest is modulated by pre-patterned cSfrp2 expression and a WNT-BMP signalling loop.

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