Trends in Neurosciences
Research updateArRAnging the hindbrain
Section snippets
Rolling chicks provide a unifying framework
Recently [13], a chicken embryo in vitro culture system was used to address many of the remaining uncertainties. Chicken embryos were cultured from as early as the full primitive streak stage (stage 4) in roller tubes containing culture medium for up to 30 hours. This approach allows for treatments at different stages with precise amounts of the pan-RAR synthetic retinoid antagonist BMS493. Subsequent phenotypic analysis relied on molecular markers specific for each rhombomere (Box 1).
Treatment
Time windows of specification
By blocking RA signalling at different stages with saturating amounts (5 μm) of the RA antagonist [13] it could be determined whether there are distinct developmental time windows during which distinct rhombomeres are specified by RA.
The results showed that specification and correct AP positioning of rhombomeres r3–r8 takes place between chick stages 5–10+ following a strict rostrocaudal sequence. Rhombomeres 3 and 4 require RA for correct AP positioning but not for specification. Each of the
Higher RA signalling for more posterior rhombomeres
The analysis of rat embryos obtained from VAD females gave the first solid evidence that increasing amounts of retinoids are required for correct specification of more posterior rhombomeres [9]. The chick in vitro-culture system allowed these observations to be extended to another species and the RA signalling required in situ to be quantitatively estimated. Treatment of chick embryos at a fixed early stage with decreasing amounts of the antagonist allowed the progressive specification of more
(Re)interpretations and (new) insights
Expansion of hindbrain molecular markers in chicken embryos with partial or full block of RA signalling spread up to, but never transcended, the r8/spinal cord boundary (Fig. 1,Fig. 2). Cells rostral to this level have the broad ectomesenchymal potential of cranial neural crest. This region is included in the skull and members of the Delta/Notch pathway have sharp caudal expression boundaries in that region [17]. By these criteria, this boundary corresponds to the postulated caudal hindbrain
Conclusion
It is now clear that RA is at the top of the genetic hierarchy that specifies the caudal hindbrain. Direct links between RA and several Hox genes involved in hindbrain patterning have been established 21, 23, 24, but it is still not known whether RA also directly regulates expression of key segmentation genes such as Krox20 and MafB/kr in r5 and r5/r6, respectively. It will be challenging to elucidate the connections in the RA genetic hierarchy, because each player in it could distribute to and
Acknowledgements
A. Gavalas was supported by an EMBO long-term postdoctoral fellowship and by the Medical Research Council. Work in the author's laboratory is currently funded by a Wellcome Research Career Development Fellowship. Thanks are owed to Alex Gould and Nobue Itasaki for comments on the article.
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2020, Developmental BiologyCoordinate regulation of retinoic acid synthesis by pbx genes and fibroblast growth factor signaling by hoxb1b is required for hindbrain patterning and development
2018, Mechanisms of DevelopmentCitation Excerpt :Cyp26 (Cytochrome P450 family 26) enzymes act to inhibit RA signaling by hydroxylating RA (Abu-Abed et al., 2001; Niederreither et al., 2002) in the forebrain, midbrain, and anterior hindbrain (de Roos et al., 1999; Hernandez et al., 2004; Sakai et al., 2001; Sirbu et al., 2005; Swindell and Eichele, 1999). This creates a gradient of RA across the A-P axis of the hindbrain where higher concentrations of RA activate progressively more posterior genes (Gavalas, 2002). Reduced RA levels result in the loss of posterior hindbrain identity (Begemann et al., 2001; Dupe and Lumsden, 2001; Maden et al., 1996) while increased levels of RA disrupt the development of the anterior hindbrain (Gould et al., 1998; Hill et al., 1995; Morrison et al., 1997), with such alterations commonly ascribed to changes in hox gene expression (Ferretti et al., 2000; Frasch et al., 1995; Gould et al., 1998; Morrison et al., 1997; Papalopulu et al., 1991; Yan et al., 1998).
Hard to swallow: Developmental biological insights into pediatric dysphagia
2016, Developmental BiologySpatiotemporal mechanisms of morphogen gradient interpretation
2011, Current Opinion in Genetics and DevelopmentCitation Excerpt :There are several patterning systems in which it has been proposed that positional information is encoded in the duration of morphogen signaling. These include the patterning of rhombomeres in the zebrafish hindbrain by retinoic acid [25,26]; the specification of digits in the vertebrate limb in response to Sonic Hedgehog (Shh) signaling [27]; the specification of olfactory and lens placodal cells in the chick embryo in response to BMPs [28]; and the dorsoventral patterning of the chick neural tube by Shh [29]. The last of these examples is so far the best understood mechanistically, thanks to several recent studies [29,30,31•,32,33•].
Selective gene expression in regions of primate neocortex: Implications for cortical specialization
2011, Progress in NeurobiologyCitation Excerpt :The binding of these receptors to the RA response element (RARE) in promoter regions activates the transcription of many genes (Gudas et al., 1994; Clagett-Dame and Plum, 1997). Thus, RA is important for morphogenesis and differentiation in a number of tissues including those in the CNS: for example, in hindbrain segmentation (Gavalas, 2002) and possibly regionalization of the forebrain (LaMantia et al., 1993; Smith et al., 2001). In mice, RALDH3, one of the isotypes of RALDH, is transiently expressed in the nucleus accumbens, the olfactory bulb, and the cerebral cortex during the early postnatal period (Wagner et al., 2002).