Trends in Neurosciences
Volume 25, Issue 2, 1 February 2002, Pages 61-64
Journal home page for Trends in Neurosciences

Research update
ArRAnging the hindbrain

https://doi.org/10.1016/S0166-2236(02)02067-2Get rights and content

Abstract

The retinoic acid (RA)-dependent mechanisms that orchestrate the development of the hindbrain have been the focus of intense studies over the last decade. A wide range of model systems and experimental approaches have been used to provide important insights into hindbrain patterning. A recent paper could help to unify seemingly disparate observations across species and experimental approaches. Specification of the entire caudal hindbrain is fully dependent on retinoic acid, and specification of individual rhombomeres (r) follows a strict rostrocaudal sequence at precise developmental time windows. Progressively higher RA signalling is necessary for assigning more posterior territories. Complete RA deficiency results in the caudal hindbrain assuming an r4-like identity, which is postulated to be the hindbrain ground state.

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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