Retinoic acid establishes ventral retinal characteristics

Development ◽  
1996 ◽  
Vol 122 (1) ◽  
pp. 195-204 ◽  
Author(s):  
G.A. Hyatt ◽  
E.A. Schmitt ◽  
N. Marsh-Armstrong ◽  
P. McCaffery ◽  
U.C. Drager ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Retinoic Acid ◽  
Optic Nerve ◽  
Normal Development ◽  
Cell Content ◽  
Optic Stalk ◽  
Eye Field ◽  
Dorsal Retina ◽  
Choroid Fissure

The developing eye is known to be rich in retinoic acid (RA), and perturbations in RA levels during formation of the optic primordia, as well as RA receptor mutations, cause retinal malformations, especially in ventral eye regions. To test the hypothesis that RA plays a role in the establishment of ventral retinal characteristics, we examined several dorsal and ventral ocular markers in RA-treated zebrafish. The optic stalk represents the ventral-most region of the early eye field. During normal development, the optic stalks constrict, decreasing in width and are gradually replaced by the optic nerve. Systemic high RA levels cause an expansion in the optic stalk with an increased cell content and a patent lumen. In addition, the stalks do not constrict and persist into later stages of development indicating an enhancement of early ventral eye characteristics. Expression of the transcription factor pax[b], normally confined to the ventral retina, expands into the dorsal retina following RA treatment, whereas msh[c], normally expressed in the dorsal retinal pole, disappears. Activity of an aldehyde dehydrogenase that normally occupies the dorsal third of the retina is reduced or abolished following high systemic RA. When a localized RA source, an RA-soaked bead, is placed next to the developing eye, a fissure resembling the choroid fissure appears in the eye facing the bead. Taken together, these observations suggest that RA is involved in the determination of the ventral retina.

Novel retinoic acid generating activities in the neural tube and heart identified by conditional rescue of Raldh2 null mutant mice

Development ◽  
2002 ◽  
Vol 129 (9) ◽  
pp. 2271-2282 ◽  
Author(s):  
Felix A. Mic ◽  
Robert J. Haselbeck ◽  
Arnold E. Cuenca ◽  
Gregg Duester
Keyword(s):  
Spinal Cord ◽  
Retinoic Acid ◽  
Neural Tube ◽  
The Novel ◽  
Vertebrate Development ◽  
Targeted Disruption ◽  
Surface Ectoderm ◽  
Eye Field ◽  
Null Mutant Mice ◽  
Dorsal Retina

Retinoid control of vertebrate development depends upon tissue-specific metabolism of retinol to retinoic acid (RA). The RA biosynthetic enzyme RALDH2 catalyzes much, but not all, RA production in mouse embryos, as revealed here with Raldh2 null mutants carrying an RA-responsive transgene. Targeted disruption of Raldh2 arrests development at midgestation and eliminates all RA synthesis except that associated with Raldh3 expression in the surface ectoderm of the eye field. Conditional rescue of Raldh2–/– embryos by limited maternal RA administration allows development to proceed and results in the establishment of additional sites of RA synthesis linked to Raldh1 expression in the dorsal retina and to Raldh3 expression in the ventral retina, olfactory pit and urinary tract. Unexpectedly, conditionally rescued Raldh2–/– embryos also possess novel sites of RA synthesis in the neural tube and heart that do not correspond to expression of Raldh1-3. RA synthesis in the mutant neural tube was localized in the spinal cord, posterior hindbrain and portions of the midbrain and forebrain, whereas activity in the mutant heart was localized in the conotruncus and sinus venosa. In the posterior hindbrain, this novel RA-generating activity was expressed during establishment of rhombomeric boundaries. In the spinal cord, the novel activity was localized in the floorplate plus in the intermediate region where retinoid-dependent interneurons develop. These novel RA-generating activities in the neural tube and heart fill gaps in our knowledge of how RA is generated spatiotemporally and may, along with Raldh1 and Raldh3, contribute to rescue of Raldh2–/– embryos by producing RA locally.

scholarly journals Reconsolidation or Extinction: Transcription Factor Switch in the Determination of Memory Course after Retrieval

2011 ◽  
Vol 31 (15) ◽  
pp. 5562-5573 ◽  
Author(s):  
V. de la Fuente ◽  
R. Freudenthal ◽  
A. Romano
Keyword(s):  
Transcription Factor

scholarly journals DNA methylation changes are a late event in acute promyelocytic leukemia and coincide with loss of transcription factor binding

Blood ◽  
2013 ◽  
Vol 121 (1) ◽  
pp. 178-187 ◽  
Author(s):  
Till Schoofs ◽  
Christian Rohde ◽  
Katja Hebestreit ◽  
Hans-Ulrich Klein ◽  
Stefanie Göllner ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Transcription Factor ◽  
Retinoic Acid ◽  
Acute Promyelocytic Leukemia ◽  
Binding Sites ◽  
Embryonic Stem ◽  
Transcription Factor Binding ◽  
Promyelocytic Leukemia ◽  
Factor Binding ◽  
Aberrant Dna Methylation

Abstract The origin of aberrant DNA methylation in cancer remains largely unknown. In the present study, we elucidated the DNA methylome in primary acute promyelocytic leukemia (APL) and the role of promyelocytic leukemia–retinoic acid receptor α (PML-RARα) in establishing these patterns. Cells from APL patients showed increased genome-wide DNA methylation with higher variability than healthy CD34+ cells, promyelocytes, and remission BM cells. A core set of differentially methylated regions in APL was identified. Age at diagnosis, Sanz score, and Flt3-mutation status characterized methylation subtypes. Transcription factor–binding sites (eg, the c-myc–binding sites) were associated with low methylation. However, SUZ12- and REST-binding sites identified in embryonic stem cells were preferentially DNA hypermethylated in APL cells. Unexpectedly, PML-RARα–binding sites were also protected from aberrant DNA methylation in APL cells. Consistent with this, myeloid cells from preleukemic PML-RARα knock-in mice did not show altered DNA methylation and the expression of PML-RARα in hematopoietic progenitor cells prevented differentiation without affecting DNA methylation. Treatment of APL blasts with all-trans retinoic acid also did not result in immediate DNA methylation changes. The results of the present study suggest that aberrant DNA methylation is associated with leukemia phenotype but is not required for PML-RARα–mediated initiation of leukemogenesis.

scholarly journals Transcription factor GATA-4 regulates cardiac muscle-specific expression of the alpha-myosin heavy-chain gene.

1994 ◽  
Vol 14 (7) ◽  
pp. 4947-4957 ◽  
Author(s):  
J D Molkentin ◽  
D V Kalvakolanu ◽  
B E Markham
Keyword(s):  
Skeletal Muscle ◽  
Transcription Factor ◽  
Retinoic Acid ◽  
Cardiac Muscle ◽  
Myosin Heavy Chain ◽  
Heavy Chain ◽  
Binding Sites ◽  
Ectopic Expression ◽  
Specific Expression ◽  
Cardiac Phenotype

The alpha-myosin heavy-chain (alpha-MHC) gene is the major structural protein in the adult rodent myocardium. Its expression is restricted to the heart by a complex interplay of trans-acting factors and their cis-acting sites. However, to date, the factors that have been shown to regulate expression of this gene have also been found in skeletal muscle cells. Recently, transcription factor GATA-4, which has a tissue distribution limited to the heart and endodermally derived tissues, was identified. We recently found two putative GATA-binding sites within the proximal enhancer of the alpha-MHC gene, suggesting that GATA-4 might regulate its expression. In this study, we establish that GATA-4 interacts with the alpha-MHC GATA sites to stimulate cardiac muscle-specific expression. Mutation of the GATA-4-binding sites either individually or together decreased activity by 50 and 88% in the adult myocardium, respectively. GATA-4-dependent enhancement of activity from a heterologous promoter was mediated through the alpha-MHC GATA sites. Coinjection of an alpha-MHC promoter construct with a GATA-4 expression vector permitted ectopic expression in skeletal muscle but not in fibroblasts. Thus, the lack of alpha-MHC expression in skeletal muscle correlates with a lack of GATA-4. GATA-4 DNA binding activity was significantly up-regulated in triiodothyronine- or retinoic acid-treated cardiomyocytes. Putative GATA-4-binding sites are also found in the regulatory regions of other cardiac muscle-expressed structural genes. This indicates a mechanism whereby triiodothyronine and retinoic acid can exert coordinate control of the cardiac phenotype through a trans-acting regulatory factor.

Fibre order in the normal Xenopus optic tract, near the chiasma

Development ◽  
1984 ◽  
Vol 83 (1) ◽  
pp. 1-14
Author(s):  
J. W. Fawcett ◽  
J. S. H. Taylor ◽  
R. M. Gaze ◽  
P. Grant ◽  
E. Hirst
Keyword(s):  
Optic Nerve ◽  
Small Groups ◽  
Optic Nerve Head ◽  
Tritiated Thymidine ◽  
Optic Tract ◽  
Peripheral Retina ◽  
Retinal Lesions ◽  
Dorsal Retina

In juvenile Xenopus retinotopic fibre order in the optic tract near the chiasma was investigated by labelling small groups of optic fibres from peripheral retina with HRP. This selective fibre labelling with HRP was combined with autoradiography following administration of tritiated thymidine to the eye, so that the HRP-labelled fibres could be located within the borders of the optic tract. Fibres arising from the periphery of all four retinal quadrants were superficially located in the optic tract near the chiasma, with dorsal retinal fibres showing the greatest tendency to travel deep in the diencephalon. Retinal lesions closer to the optic nerve head labelled fibres which ran deeper in the optic tract. Near the chiasma, fibres from ventral retina tended to group rostrally while fibres from dorsal retina tended to group caudally. However, no obvious localization of fibres arising in temporal or nasal retina was seen in the lower optic tract.

Transcription factor Sp1 is important for retinoic acid-induced expression of the tissue plasminogen activator gene during F9 teratocarcinoma cell differentiation

1990 ◽  
Vol 10 (11) ◽  
pp. 5883-5893
Author(s):  
A L Darrow ◽  
R J Rickles ◽  
L T Pecorino ◽  
S Strickland
Keyword(s):  
Transcription Factor ◽  
Retinoic Acid ◽  
Cyclic Amp ◽  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Differentiated Cells ◽  
Cell Extracts ◽  
Transcription Factor Sp1 ◽  
Tissue Plasminogen

The induced differentiation of F9 cells by retinoic acid (RA) and cyclic AMP (cAMP) activated transcription of the tissue plasminogen activator (t-PA) gene. This differentiation-responsive regulation of the t-PA promoter was also observed in transient assays. Multiple sequence elements within 243 bp of t-PA DNA contributed to the high level of transcription in retinoic acid- and cyclic AMP-differentiated cells. To investigate the factors involved in controlling t-PA transcription upon differentiation, we used F9 cell extracts to examine proteins that bind two proximal promoter elements. These elements (boxes 4 and 5) are homologous to GC boxes that are known binding sites for transcription factor Sp1. Mobility shift assays in the presence and absence of anti-Sp1 antibodies demonstrated that the proteins which bound to this region were immunologically related to human Sp1. The proteins also had a DNA-binding specificity similar to that of a truncated form of Sp1. Mutations of the GC motif within boxes 4 and 5 that interfered with Sp1 binding reduced in parallel the binding of the F9 cellular factors and lowered transcription in vitro as well as in vivo. Although this proximal region of the t-PA promoter was active in vivo only in differentiated cells, the Sp1-like binding proteins were present in equal concentrations and had similar properties in extracts of both stem and differentiated cells. These data suggest that other cellular elements participate with this Sp1-like factor in controlling differentiation-specific expression.

Pathways of regenerated retinotectal axons in goldfish

Development ◽  
1986 ◽  
Vol 93 (1) ◽  
pp. 1-28
Author(s):  
Claudia A. O. Stuermer
Keyword(s):  
Optic Nerve ◽  
Retinal Ganglion Cells ◽  
Normal Development ◽  
Ganglion Cells ◽  
Optic Tract ◽  
Spatiotemporal Pattern ◽  
Retinal Ganglion ◽  
Retinal Axons ◽  
Age Related ◽  
Regenerated Fibres

This study investigates the order of regenerating retinal axons in the goldfish. The spatiotemporal pattern of axon regrowth was assessed by applying horseradish peroxidase (HRP) to regenerating axons in the optic tract at various times after optic nerve section and by analysing the distribution of retrogradely labelled ganglion cells in retina. At all regeneration stages labelled ganglion cells were widely distributed over the retina. There was no hint that axons from central (older) ganglion cells might regrow earlier, and peripheral (younger) ganglion cells later, as occurs in normal development. The absence of an age-related ordering in the regenerated optic nerve was demonstrated by labelling a few axon bundles intraorbitally with HRP (Easter, Rusoff & Kish, 1981) caudal to the previous cut. The retrogradely labelled cells in retina were randomly distributed in regenerates andnot clustered in annuli as in normals. Tracing regenerating axons which were stained anterogradelyfrom intraretinal HRP applications or retrogradely from single labelled tectal fascicles illustrated the fact that the regenerating axons coursed in abnormal routes in the optic nerve and tract. On the surface of the tectum regenerated fibres re-established a fascicle fan. The retinal origin of tectal fascicles was assessed by labelling individual peripheral, intermediate and rostral fascicles with HRP. The retrogradely labelled ganglion cells in the retina were often more widely distributed than in normals, but were mostly found in peripheral, intermediate and central retina, respectively. The order of fibre departure from each tectal fascicle was revealed by placing HRP either on the fascicle's proximal or on its distal half. With proximal labelling sites labelled ganglion cells were found in the temporal and nasal retina, and with distal labelling sites labelled ganglion cells were confined to nasal retina only. Further, the axonal trajectories of anterogradely labelled dorsotemporal retinal ganglion cells were compared to those of dorsonasal retinal ganglion cells in tectal whole mounts. Dorsotemporal axons were confined to the rostral tectal half, whereas dorsonasal axons followed fascicular routes into the fascicles' distal end and reached into caudal tectum. This suggests that the fibres exited along their fascicle's course in a temporonasal sequence. Thus in the tectum, fibres in fascicles restore a gross spatial and age-related order and tend to follow their normal temporonasal sequence of exit.

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