Retinoic acid is a potential dorsalising signal in the late embryonic chick hindbrain
© Wilson et al; licensee BioMed Central Ltd. 2007
Received: 17 August 2007
Accepted: 19 December 2007
Published: 19 December 2007
Human retinoic acid teratogenesis results in malformations of dorsally derived hindbrain structures such as the cerebellum, noradrenergic hindbrain neurons and the precerebellar system. These structures originate from the rhombic lip and adjacent dorsal precursor pools that border the fourth ventricle roofplate. While retinoic acid synthesis is known to occur in the meninges that blanket the hindbrain, the particular sensitivity of only dorsal structures to disruptions in retinoid signalling is puzzling. We therefore looked for evidence within the neural tube for more spatiotemporally specific signalling pathways using an in situ hybridisation screen of known retinoic acid pathway transcripts.
We find that there are highly restricted domains of retinoic acid synthesis and breakdown within specific hindbrain nuclei as well as the ventricular layer and roofplate. Intriguingly, transcripts of cellular retinoic acid binding protein 1 are always found at the interface between dividing and post-mitotic cells. By contrast to earlier stages of development, domains of synthesis and breakdown in post-mitotic neurons are co-localised. At the rhombic lip, expression of the mRNA for retinoic acid synthesising and catabolising enzymes is spatially highly organised with respect to the Cath1-positive precursors of migratory precerebellar neurons.
The late developing hindbrain shows patterns of retinoic acid synthesis and use that are distinct from the well characterised phase of rostrocaudal patterning. Selected post-mitotic populations, such as the locus coeruleus, appear to both make and break down retinoic acid suggesting that a requirement for an autocrine, or at least a highly localised paracrine signalling network, might explain its acute sensitivity to retinoic acid disruption. At the rhombic lip, retinoic acid is likely to act as a dorsalising factor in parallel with other roofplate signalling pathways. While its precise role is unclear, retinoic acid is potentially well placed to regulate temporally determined cell fate decisions within the rhombic lip precursor pool.
The influence of retinoic acid during early neural development has been extensively characterised . Retinoic acid is required in the formation of the rostrocaudal axis of the neural tube via Hox gene regulation [2, 3], as well as in the determination of segmental pattern within the hindbrain [4–8]. Correspondingly, the teratogenic effects of in utero exposure to Accutane (13-cis-retinoic acid) in humans primarily target the hindbrain : malformations include cystic dilation of the roof of the fourth ventricle, cerebellar vermis dysplasia and/or small cerebellar hemispheres, as well as defects in the inferior medullary olivary and pontine nuclei. Experimental manipulations in mouse, rat and zebrafish show that late-born, noradrenergic nuclei also require retinoic acid for their specification [10, 11] and confirm that the cerebellum [12, 13] and its major precerebellar afferents, the inferior olive [11, 14] and pontine nuclei , are particularly sensitive to aberrant retinoid levels. This findings are complemented by observations in the RAREhsplacZ transgenic retinoic acid reporter mouse, which show that the cerebellar vermis, pontine nuclei and inferior olive are all exposed to high levels of retinoic acid signalling during their development .
It is a paradox that while retinoic acid has a clear role in early rostrocaudal patterning, it is these late-born, dorsally derived hindbrain components that are particularly sensitive to abnormal retinoic acid signals. The precerebellar system [16, 17] and various elements of the cerebellum [18–20] migrate from their birthplace at the rhombic lip, a spatially discrete precursor pool lies at the interface between the dorsal neural tube and non-neuronal roofplate of the fourth ventricle [21, 22]. Migratory inferior olive  and locus coeruleus neurons [23, 24] are born slightly further from the roofplate but adjacent to the rhombic lip. Hence, while retinoic acid has a clear role in specifying the rostrocaudal axis of the neural tube, different lines of evidence point to a separate role in patterning dorsal structures around the fourth ventricle roofplate.
For the post-segmental hindbrain, the meninges have been identified as a potent hypothetical source of retinoic acid . Nevertheless, these tissues, which blanket the neural tube, are unlikely to confer any particular specificity in dorsal signalling. For noradrenergic cells, selective sensitivity appears to reside in their expression of the retinoic acid-induced transcriptional activator AP-2 [10, 26]. For precerebellar derivatives, the effects of manipulation of retinoic acid levels have been attributed to a late change in segmental specification of the inferior olive  and a failure of tangential migration to the pons , inferring two separate roles for retinoic acid within adjacent precursor pools. However, recent results from a transectional genetic study  offer an alternative explanation. The developmental consequences of changes in retinoic acid availability for the inferior olive and pontine nucleus are complementary: deprivation causes an increase in size in the former and a decrease in the latter. This phenotype bears a remarkable similarity to that seen in the Pax6 smalleye mutant [17, 27]. The inferior olive and the pontine nuclei arise at the same rostrocaudal location at different distances from the roofplate. The Pax6 sey/sey phenotype has been attributed to a disruption in dorsoventral patterning underlying the allocation of these precursor pools. The effects of retinoic acid deprivation hence mimic a dorsoventral patterning phenotype.
These observations and the teratogenic phenotype of retinoic acid raise the possibility of a more spatiotemporally defined system of dorsal retinoic acid signalling. Consequently, we undertook a survey of the expression of transcripts of members of the retinoic acid signalling pathway. Our results suggest patterning roles for retinoic acid that are distinct from earlier hindbrain axial patterning. Specific nuclear clusters in the hindbrain and mid/hindbrain isthmic region express RNA transcripts for both synthetic and catabolic enzymes indicating hotspots of retinoic acid manufacture and usage. At the rhombic lip, microanatomical spatial expression domains suggest that roofplate-derived retinoic acid might act specifically on rhombic lip precursors as a diffusible, roofplate-derived dorsalising factor.
We processed embryos aged between embryonic (e) day 3 (stage 20, ) and e10 (stage 36) for in situ hybridisation to assess the spatial distribution of mRNA transcripts of participants in the RA-signalling pathway in the developing hindbrain: synthetic enzymes, binding and signalling proteins, and breakdown enzymes. During these stages, different cohorts of rhombic lip derivatives become specified and undergo tangential migration through the cerebellum and hindbrain [29, 30].
Retinoic acid synthesis
Retinoic acid binding and signalling
Retinoic acid signalling relies on the transport of retinoic acid to the nucleus, where it binds to nuclear receptors to initiate transcriptional control of RA-regulated genes . The availability of retinoic acid to nuclear receptors is regulated by retinoic acid binding proteins (Crabp1 and 2). However, whether Crabp binding potentiates signalling [37–39], or inhibits signalling by sequestering retinoic acid  or promoting its degradation [41, 42] is subject to debate. Within the nucleus, retinoic acid and RX receptors act heterodimerically as ligand activated transcriptional complexes. We therefore analysed the distribution of a representative binding protein, Crabp1, in relation to the mRNA transcripts of three RA-receptors.
We examined the expression of RAR and RXR retinoic acid receptors at equivalent stages. Expression of RAR receptors was uniform, widespread and essentially identical between subtypes examined (β and γ). RXRγ is widespread throughout the neural tube, while RXRβ has yet to be identified in chick. RXRα is not expressed in the CNS at these stages . In rhombomere 1, uniform expression of RAR (Fig. 4G RARγ is shown as representative) contrasts with localised high levels of RXRγ expression in the locus coeruleus (Fig. 5H). In the hindbrain, RARγ is uniformly expressed in ventricular and mantle zones and absent only from the major descending axon tracts (Fig. 5I). RXRγ expression is elevated in the ventricular layer and a small post-mitotic population in caudal hindbrain (Fig. 5J).
Retinoic acid catabolism
The breakdown of retinoic acid into 4-oxo-RA, 4-OH-RA, 18-OH-RA, and 5, 8-epoxy-retinoic acid occurs via the action of members of the P450 superfamily of Cyp26 enzymes [44–46]. We analysed the expression of the three family members identified so far in chick: Cyp26A1, Cyp26B1 and Cyp26C1.
Retinoid signalling at the rhombic lip
Within the e5 neural tube, the retinoic acid synthetic enzyme Cyp1B1 is expressed only at the rhombic lip (Fig. 9C) and within blood vessels. Its expression domain in dorsal neural tube precisely matches that of Gdf7 (Fig. 9D) and does not overlap with that of Cath1. The retinoic acid breakdown enzymes Cyp26A1 (Fig. 9E, F) and Cyp26C1 (Fig. 9G, H) share an identical expression pattern which encompasses the roofplate and abuts the rhombic lip. Cyp26B1 is widely expressed in the ventricular layer of the neural tube (Fig. 9I). However, as with Cyp26A1 and Cyp26C1, expression is excluded from the Cath1-positive rhombic lip (Fig. 9J). Similarly, transcripts of the retinoic acid binding protein, Crabp1, are highly expressed in the region surrounding the rhombic lip (Fig. 9K). The domain of Crabp1 precisely abuts the boundary of the Cath1-positive precursor domain with a tail of expression extending under the pial surface that matches an extension of Cath1 in tangentially migrating cells (Fig. 9L). Injections of BrdU into the neural tube followed by a short (30 minute) survival time reveal s-phase cells adjacent to the layer of Crabp1 indicating that Crabp1 is expressed in recently post-mitotic cells (Fig. 9M, N). In summary, the various transcripts of retinoic acid pathway proteins are expressed in tissues adjacent to the rhombic lip, but are specifically excluded from the pool of Cath1-positive rhombic lip precursors.
Retinoic acid signalling components in selected postmitotic hindbrain and isthmic structures
Caudal hindbrain nuclei
Retinoic acid pathway component
Retinoic acid at the rhombic lip
The rhombic lip is a site of active retinoic acid usage and experimental alterations of retinoic acid levels can profoundly influence production of rhombic lip derivatives [14, 15]. However, the assumption that these effects can be traced to late alterations in Hox gene expression and hence axial patterning  are confounded by recent studies of Pax6 function at the rhombic lip in the mouse . These analyses infer that the complementary size changes in the inferior olive and pontine nuclei produced by retinoic acid treatment or deprivation might reflect alterations in the dorsoventral allocation of cell fate at the rhombic lip.
'Source and sink' models for the action of retinoic acid based on the distribution of synthetic and catabolic enzymes have been proposed for several systems throughout embryonic development [35, 46, 50–52]. Figure 10A summarises the results of expression studies of transcripts at the rhombic lip. Transcripts of the retinoic acid synthetic enzymes Raldh2 and Cyp1B1 are found in the meninges, but also the roofplate and specifically the boundary region between neural and non-neural ectoderm adjacent to the rhombic lip. Breakdown of retinoic acid occurs in the ventricular zone (Cyp26B1) and the roofplate (Cyp26A1 and Cyp26B1) but not within Cath1-positive cells. Our results hence indicate that the roofplate is a source for retinoic acid, with potential sinks surrounding, but excluded from, the rhombic lip. Retinoic acid binding protein Crabp1 message is found at the interface between dividing cell nuclei and the mantle layer and appears to match the initial stream of tangential migration away from the rhombic lip (Fig. 10B). This suggests that the transcription of Crabp1 accompanies exit from the cell cycle. The precise role of Crabp1 in signalling is unclear, either indicating an active transportation and hence utilization of retinoic acid in the nucleus [37–39], or conversely a reduction in the availability of cellular retinoic acid by sequestration  or degradation [41, 42]. Cells are either activating retinoic acid signalling precisely as they exit the proliferative zone or buffering its further effects (Fig. 10C). An answer to this important question will require a further examination of the role of both Crabp1 and 2 at this transition zone. In either case, our findings correspond with significant activation of Lacz in the rhombic lip of the RAREhsplacZ transgenic mouse. We propose that the supply of retinoic acid to the rhombic lip is regulated by a localised gradient from the roofplate.
What are the potential roles of retinoic acid as a diffusible dorsalising factor? Cath1 itself is induced by BMP signals [53, 54] downstream of roofplate determinants such as the Lmx1 genes [55, 56]. It seems unlikely that retinoic acid has a role in inducing Cath1 and hence the rhombic lip although our "source/sink" model argues that the primary actions of retinoic acid are within this precursor pool. More consistent with reported functions in other systems would be a function in regulating either the timing of cell cycle exit [57, 58] or fate determination [1, 59–61]. Cell birth date and fate are intricately linked in the developing rhombic lip with a precise sequence of different populations  produced from the same pool of Atonal1(Cath1)-positive cells [18, 19]. We have recently shown that the transition between temporal fates requires a unidentified signal external to the rhombic lip . Retinoic acid would provide an excellent candidate for such a signal, regulating the progression of cell fate transitions.
If the primary effects of roofplate derived retinoic acid lie within the Cath1-positive rhombic lip domain, our model implies that the changes in size of the inferior olive seen with experimental retinoic acid manipulation are either secondary, or via a roofplate-independent source of retinoic acid such as the meninges . The inferior olive precursor pool lies within the dorsal Wnt1-positive domain  but outside to the Cath1-positive rhombic lip . While we cannot exclude a role for the meninges, inferior olive size is likely to reflect both the expression of Pax6 at the rhombic lip and mechanisms of cross-repression between proliferating pools. Firstly, retinoic acid within the fourth ventricle roofplate might induce the late, spatially restricted dorsal expression of Pax6 at the rhombic lip; loss of Pax6 [17, 27] appears to mimic the effects of retinoic acid deprivation [14, 15]. Alternatively, an increase in inferior olive size may be secondary to disruptions in the rhombic lip. Cross-repression between respective precursor pools within the Wnt1 domain has been proposed as a factor that regulates inferior olive size .
Sources and sinks of retinoic acid in late developing hindbrain and isthmic region
Outside the rhombic lip, the proliferative ventricular layer of the hindbrain can be characterized as a patchwork retinoic acid sink by its expression of Cyp26B1 in defined blocks of dividing cells. Transcripts of the retinoic acid binding protein, Crabp1, characterize the interface between ventricular zone and mantle layer. As at the rhombic lip, Crabp1 is likely to be significant in transiently facilitating or terminating intracellular retinoic acid signalling as cells drop out of division.
Outside pools of proliferating cells we find significant "hotspots" of potential retinoic acid signalling in subsets of neurons. Moreover, while in the early embryo the potential sources and sinks of retinoic acid are topographically complementary, there is considerable convergence of expression of retinoic acid pathway transcripts onto a relatively small number of nuclear locations (Table 1). This suggests spatially highly localized or even autocrine retinoic acid signalling. For example, the locus coeruleus is a physiologically significant noradrenergic nucleus with widespread connections throughout the CNS, which is derived from dorsal neural tube [23, 24]. Retinoic acid potentiates noradrenalin production by the induction of AP-2, which regulates the transcription of both tyrosine hydroxylase and dopamine beta hydroxylase [10, 26]. In this study, we show that the noradrenergic locus coeruleus is not only a potential sink for retinoic acid but also a source of its production by the expression of RXRγ/Cyp26B1 and Raldh1, respectively.
Similarly the isthmo-optic region of the caudal midbrain, the vestibuloacoustic nuclei of the hindbrain, and likely noradrenergic nuclei of the caudal hindbrain are both sources and sinks of retinoic acid. Of these, midbrain and vesitbuloacoustic structures have as yet no reported sensitivity to aberrant retinoic acid levels. Finally, a potentially significant source of retinoic acid for both midbrain and anterior cerebellum is the midbrain/hindbrain isthmus. In this case, it is significant that the mammalian cerebellar vermis, which is derived from territory close to the isthmus , is both a site of high retinoic acid availability  and is specifically affected by exposure to retinoic acid [9, 12, 13].
The evidence of highly localised signalling within defined postmitotic hindbrain nuclei suggests that retinoic acid is required for the maintenance of these structures. This would explain why specific populations of hindbrain neurons are particularly sensitive to abnormal retinoic acid levels during late development. As with the rhombic lip, this close analysis of retinoic acid pathway transcripts in the remainder of the hindbrain and isthmus reduces a hypothetical requirement for sources of retinoic acid in the meninges  or external to the neural tube such as the Raldh3-positive inner ear (Fig. 3) and the cranial mesoderm, which expresses Cyp1B1 (Fig. 4). The localized sources of retinoic acid production and breakdown that we have identified in this study suggest the possibility of a far more spatially precise signalling system in the late embryonic hindbrain and isthmus.
The localisation of retinoic acid signalling components in the late developing hindbrain strongly suggests that spatially organised retinoic acid is important in the maintenance of several late-developing neuronal populations such as the locus coeruleus. In addition, we propose that the precise location and spatiotemporal arrangement of retinoic acid pathway transcripts around the rhombic lip and roofplate of the fourth ventricle indicate that retinoic acid is a potential roofplate derived dorsalising factor in the hindbrain (Fig. 10). In this context, retinoic acid is an excellent candidate for regulating the orderly temporal sequence of cell fate changes within the rhombic lip that characterise the production of both its precerebellar and cerebellar derivatives.
Embryo collection and staging
Embryos were incubated at 37°C and harvested in phosphate buffered saline at e3–e10. Dissected neural tissue was fixed in 4% paraformaldehyde and stored at 4°C. Embryos were staged (st.) according to Hamburger and Hamilton  along with the corresponding embryonic days of development, such that: e3 = st.20, e4 = st.24, e5 = st.27, e6 = st.29, e7 = st.31, e8 = st.34, e10 = st.36.
BrdU labelling was carried out as previously described (Myat et al., 1996). Embryos were incubated for a 30 minutes following BrdU injection and then fixed in 4% paraformaldehyde
In situ hybridisation and immunohistochemistry
Tissue was processed for in situ hybridisation using standard protocols  with DIG- and fluorescein-labelled riboprobes for a number of genes:, RARγ, RXRγ (gift of Paul Brickell), RARβ (gift of Gregor Eichele), Raldh1, Raldh2, Raldh3, Cyp1B1, Cyp26A1, Cyp26B1, Cyp26C1 , Cath1 , Tyrosine hydroxylase , Tlx3 (gift of Cairine Logan), Gdf7 (gift of Anthony Graham), mafB, Phox2a. At least 15 embryos were processed for each probe and combination of probes in at least three separate experiments. There was no variability in patterns of labelling between experiments. After staining, selected embryos were embedded in 20% gelatin, and sectioned at 40–60 μm on a Leica vibratome. Tissue that had incorporated BrdU was processed with an anti-BrdU monoclonal antibody (Serotec) at 1:40 and an AlexaFluor488 conjugated goat anti-rat secondary antibody (Invitrogen) at 1:50.
Wholemount embryos were digitally imaged on a Leica stereo photomicroscope equipped with epifluorescence. Images of sections were captured using a Zeiss Axiocam fitted to a Zeiss Axiophot microscope. Confocal images were acquired using an Olympus Fluoview laser scanning microscope.
This work was carried out in a Medical Research Council Centre and supported by a project grant from the Wellcome Trust to RW and MM.
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