Role of a Conserved Retinoic Acid Response Element in Rhombomere Restriction of
            <i>Hoxb-1</i>

Studer, Michèle; Pöpperl, Heike; Marshall, Heather; Kuroiwa, Atsushi; Krumlauf, Robb

doi:10.1126/science.7916164

Cited by 263 publications

(172 citation statements)

References 41 publications

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“…Fewer examples of position-dependent transcription because of negative regulation exist in mammals, but such regulation does occur. For example, position-dependent Hoxd-11 and Hoxb1 gene activation involves the interplay of positive and negative elements (24,25). The highly restricted position-dependent activity of EIII in the adult liver, in contrast to EIII activity in all hepatocytes in the fetal liver, led us to ask whether negative regulation led to this developmental change in EIII activity.…”

Section: Discussionmentioning

confidence: 99%

Position-dependent activity of α-fetoprotein enhancer element III in the adult liver is due to negative regulation

Peyton

Ramesh

Spear

2000

Proc. Natl. Acad. Sci. U.S.A.

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␣-Fetoprotein (AFP) transcription is activated early in hepatogenesis, but is dramatically repressed within several weeks after birth. AFP regulation is governed by multiple elements including three enhancers termed EI, EII, and EIII. All three AFP enhancers continue to be active in the adult liver, where EI and EII exhibit high levels of activity in pericentral hepatocytes with a gradual reduction in activity in a pericentral-periportal direction. In contrast to these two enhancers, EIII activity is highly restricted to a layer of cells surrounding the central veins. To test models that could account for position-dependent EIII activity in the adult liver, we have analyzed transgenes in which AFP enhancers EII and EIII were linked together. Our results indicate that the activity of EIII is dominant over that of EII, indicating that EIII is a potent negative regulatory element in all hepatocytes except those encircling the central veins. We have localized this negative activity to a 340-bp fragment. This suggests that enhancer III may be involved in postnatal AFP repression.T he ␣-fetoprotein (AFP) gene, which encodes the major serum protein in the developing mammalian fetus, is transcribed in the yolk sac visceral endoderm, fetal liver, and, to a much lesser extent, in the fetal gut and kidney (1). AFP activation during hepatogenesis occurs as primordial hepatocytes migrate out from the developing foregut (2). The AFP gene continues to be expressed abundantly in hepatocytes during development, but is dramatically repressed postnatally (3); in the liver, this represents a nearly 10,000-fold reduction in transcription (3). The AFP gene is normally expressed at extremely low levels in the adult liver, but can be reactivated during periods of renewed cell growth such as during liver regeneration and in hepatocellular carcinomas (4).Perinatal AFP repression does not occur uniformly in all hepatocytes. Rather, reduced AFP mRNA levels are first seen in hepatocytes that reside in the perivenous regions of the liver, i.e., those cells surrounding the portal triads. AFP repression continues in a gradient-like fashion in a perivenous to pericentral direction (5, 6). Thus, the last cells to express AFP before complete shut-off reside in a single layer of hepatocytes surrounding the central veins. In addition to AFP repression, other transcriptional changes occur in the perinatal liver. In particular, the mRNAs for numerous liver enzymes become zonally expressed, i.e., synthesized exclusively in pericentral or perivenous hepatocytes (reviewed in ref. 7). For example, glutamine synthetase and ornithine aminotransferase are expressed exclusively in a narrow band of cells surrounding the central veins (8-10).Other enzymes, such as carbamoylphosphate synthetase and ornithine transcarbamylase, are expressed in a broad band of hepatocytes encircling the portal triads (10, 11). These periportal and pericentral regions of expression are nonoverlapping. The basis for this position-dependent regulation is not known, but a mathematica...

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Section: Discussionmentioning

confidence: 99%

Position-dependent activity of α-fetoprotein enhancer element III in the adult liver is due to negative regulation

Peyton

Ramesh

Spear

2000

Proc. Natl. Acad. Sci. U.S.A.

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“…Our results suggest that if these RAREs respond to RA in vivo, they do so only within an established pattern of expression; there is no expansion of the expression domains of either gene in response to all-trans RA. Perhaps the retinoid responsiveness and basal expression of genes containing distinct RAREs are regulated by other mechanisms or factors in a complex tissue that is not available in a homogeneous cultured cell population (see also Studer et al, 1994). Such diversity in the regulation of retinoid responses would increase the range of potential consequences for retinoid signaling during regional and cellular differentiation.…”

Section: Rare-tk-p-gal Transgene Detects a Distinct Type Of Retinoid mentioning

confidence: 99%

Retinoid signaling and the generation of regional and cellular diversity in the embryonic mouse spinal cord

Colbert

Rubin

Linney

et al. 1995

Developmental Dynamics

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“…RA directly regulates gene expression through its nuclear hormone receptor (RAR) and co-receptor (RXR), which bind RA response elements (RAREs) in the enhancers of target genes (Bastien and Rochette-Egly, 2004). In the hindbrain, RA regulates the expression of 3Ј-Hox genes through direct (in the case of Hox-1 and Hox-4 genes) or indirect (in the case of Hox-3 genes) mechanisms (Gould et al, 1998;Hernandez et al, 2004;Marshall et al, 1994;Nolte et al, 2003;Studer et al, 1994;Zhang et al, 2000). Other anterior RAresponsive genes (Hox-1 family genes) are expressed earlier and at lower RA concentrations than the more-posterior RA-responsive genes (Hox-4 family genes) (Dupe and Lumsden, 2001;Maves and Kimmel, 2005;Simeone et al, 1990).…”

Section: Introductionmentioning

confidence: 99%

Cyp26 enzymes generate the retinoic acid response pattern necessary for hindbrain development

et al. 2007

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Retinoic acid (RA) is essential for normal vertebrate development,including the patterning of the central nervous system. During early embryogenesis, RA is produced in the trunk mesoderm through the metabolism of vitamin A derived from the maternal diet and behaves as a morphogen in the developing hindbrain where it specifies nested domains of Hox gene expression. The loss of endogenous sources of RA can be rescued by treatment with a uniform concentration of exogenous RA, indicating that domains of RA responsiveness can be shaped by mechanisms other than the simple diffusion of RA from a localized posterior source. Here, we show that the cytochrome p450 enzymes of the Cyp26 class, which metabolize RA into polar derivatives,function redundantly to shape RA-dependent gene-expression domains during hindbrain development. In zebrafish embryos depleted of the orthologs of the three mammalian CYP26 genes CYP26A1, CYP26B1 and CYP26C1, the entire hindbrain expresses RA-responsive genes that are normally restricted to nested domains in the posterior hindbrain. Furthermore,we show that Cyp26 enzymes are essential for exogenous RA to rescue hindbrain patterning in RA-depleted embryos. We present a `gradient-free' model for hindbrain patterning in which differential RA responsiveness along the hindbrain anterior-posterior axis is shaped primarily by the dynamic expression of RA-degrading enzymes.

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Role of a Conserved Retinoic Acid Response Element in Rhombomere Restriction of Hoxb-1

Cited by 263 publications

References 41 publications

Position-dependent activity of α-fetoprotein enhancer element III in the adult liver is due to negative regulation

Position-dependent activity of α-fetoprotein enhancer element III in the adult liver is due to negative regulation

Retinoid signaling and the generation of regional and cellular diversity in the embryonic mouse spinal cord

Cyp26 enzymes generate the retinoic acid response pattern necessary for hindbrain development

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