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Retinoic acid is a potential dorsalising signal in the late embryonic chick hindbrain.

Wilson LJ, Myat A, Sharma A, Maden M, Wingate RJ - BMC Dev. Biol. (2007)

Bottom Line: Intriguingly, transcripts of cellular retinoic acid binding protein 1 are always found at the interface between dividing and post-mitotic cells.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: MRC Centre for Developmental Neurobiology, King's College London, 4th floor New Hunt's House, Guy's Campus, London SE1 1UL, UK. leigh.wilson@kcl.ac.uk

ABSTRACT

Background: 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.

Results: 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.

Conclusion: 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.

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Expression of Cyp26C1. A. At e3.5, expression characterises the roof plate, rhombic lip and ventral hindbrain (out of focal plane). B. Transverse section through caudal rhombomere 1 showing roof plate expression (arrow). C. Transverse section through the caudal hindbrain (dashed line in A) showing expression in the roof plate, rhombic lip and in cells adjacent to the floor plate. D. Expression at e5 is similar to that at e3.5. E. Transverse section at the level of rhombomere 4 shows that ventral Cyp26C1 expression is limited to the ventricular layer. F. In addition, at the level of rhombomeres 5 and 6, Cyp26C1 characterises a discrete column of post-mitotic neurons (arrow). G. Rat e6.5, a dorsal view of the hindbrain shows Cyp26C1 is still present in the roofplate. H. Ventral view of the same hindbrain shows three ventrolateral Cyp26C1-positive populations in the caudal hindbrain. I. Transverse section through fourth ventricle roof plate (indicated in G). J, K, L. Transverse sections through the caudal hindbrain at positions indicated in H show expression coincident with elevated levels of RXRγ (Fig. 5J).
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Figure 8: Expression of Cyp26C1. A. At e3.5, expression characterises the roof plate, rhombic lip and ventral hindbrain (out of focal plane). B. Transverse section through caudal rhombomere 1 showing roof plate expression (arrow). C. Transverse section through the caudal hindbrain (dashed line in A) showing expression in the roof plate, rhombic lip and in cells adjacent to the floor plate. D. Expression at e5 is similar to that at e3.5. E. Transverse section at the level of rhombomere 4 shows that ventral Cyp26C1 expression is limited to the ventricular layer. F. In addition, at the level of rhombomeres 5 and 6, Cyp26C1 characterises a discrete column of post-mitotic neurons (arrow). G. Rat e6.5, a dorsal view of the hindbrain shows Cyp26C1 is still present in the roofplate. H. Ventral view of the same hindbrain shows three ventrolateral Cyp26C1-positive populations in the caudal hindbrain. I. Transverse section through fourth ventricle roof plate (indicated in G). J, K, L. Transverse sections through the caudal hindbrain at positions indicated in H show expression coincident with elevated levels of RXRγ (Fig. 5J).

Mentions: Cyp26C1 expression shares characteristics of both Cyp26A1 and Cyp26B1. At e3.5, Cyp26C1 is expressed in the roof plate of the fourth ventricle and at the rhombic lip (Fig. 8A). Ventrally, Cyp26C1 is expressed in a segmentally organised ventricular domain. Transverse sections show, as with Cyp26A1, that Cyp26C1 is expressed only in the roofplate and not the overlying meninges (Fig. 8B). It is most highly expressed at the interfaces between the neural tube and its midline structures, the roofplate and the floorplate (Fig. 8C). This expression is maintained to e5 (Fig. 8D). In transverse section, the ventral ventricular domains of Cyp26C1 hindbrain expression (Fig. 8E) are similar to those of Cyp26B1. Similarly, in only rhombomeres 5 and 6, Cyp26C1 is expressed in a column of post-mitotic neurons (Fig. 8F). At e6.5, expression of Cyp26C1 is still present within the roof plate (Fig. 8G) but down-regulated in dividing neural precursors. In the hindbrain, expression is found in three discrete nuclear clusters (Fig. 8H). Transverse sections show that expression of Cyp26C1 in the roofplate does not spread to the meninges (Fig. 8I) and that labelled hindbrain nuclei form a contiguous column (Fig. 8K–L) which correspond with higher levels of RXRγ (Fig. 5J).


Retinoic acid is a potential dorsalising signal in the late embryonic chick hindbrain.

Wilson LJ, Myat A, Sharma A, Maden M, Wingate RJ - BMC Dev. Biol. (2007)

Expression of Cyp26C1. A. At e3.5, expression characterises the roof plate, rhombic lip and ventral hindbrain (out of focal plane). B. Transverse section through caudal rhombomere 1 showing roof plate expression (arrow). C. Transverse section through the caudal hindbrain (dashed line in A) showing expression in the roof plate, rhombic lip and in cells adjacent to the floor plate. D. Expression at e5 is similar to that at e3.5. E. Transverse section at the level of rhombomere 4 shows that ventral Cyp26C1 expression is limited to the ventricular layer. F. In addition, at the level of rhombomeres 5 and 6, Cyp26C1 characterises a discrete column of post-mitotic neurons (arrow). G. Rat e6.5, a dorsal view of the hindbrain shows Cyp26C1 is still present in the roofplate. H. Ventral view of the same hindbrain shows three ventrolateral Cyp26C1-positive populations in the caudal hindbrain. I. Transverse section through fourth ventricle roof plate (indicated in G). J, K, L. Transverse sections through the caudal hindbrain at positions indicated in H show expression coincident with elevated levels of RXRγ (Fig. 5J).
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Figure 8: Expression of Cyp26C1. A. At e3.5, expression characterises the roof plate, rhombic lip and ventral hindbrain (out of focal plane). B. Transverse section through caudal rhombomere 1 showing roof plate expression (arrow). C. Transverse section through the caudal hindbrain (dashed line in A) showing expression in the roof plate, rhombic lip and in cells adjacent to the floor plate. D. Expression at e5 is similar to that at e3.5. E. Transverse section at the level of rhombomere 4 shows that ventral Cyp26C1 expression is limited to the ventricular layer. F. In addition, at the level of rhombomeres 5 and 6, Cyp26C1 characterises a discrete column of post-mitotic neurons (arrow). G. Rat e6.5, a dorsal view of the hindbrain shows Cyp26C1 is still present in the roofplate. H. Ventral view of the same hindbrain shows three ventrolateral Cyp26C1-positive populations in the caudal hindbrain. I. Transverse section through fourth ventricle roof plate (indicated in G). J, K, L. Transverse sections through the caudal hindbrain at positions indicated in H show expression coincident with elevated levels of RXRγ (Fig. 5J).
Mentions: Cyp26C1 expression shares characteristics of both Cyp26A1 and Cyp26B1. At e3.5, Cyp26C1 is expressed in the roof plate of the fourth ventricle and at the rhombic lip (Fig. 8A). Ventrally, Cyp26C1 is expressed in a segmentally organised ventricular domain. Transverse sections show, as with Cyp26A1, that Cyp26C1 is expressed only in the roofplate and not the overlying meninges (Fig. 8B). It is most highly expressed at the interfaces between the neural tube and its midline structures, the roofplate and the floorplate (Fig. 8C). This expression is maintained to e5 (Fig. 8D). In transverse section, the ventral ventricular domains of Cyp26C1 hindbrain expression (Fig. 8E) are similar to those of Cyp26B1. Similarly, in only rhombomeres 5 and 6, Cyp26C1 is expressed in a column of post-mitotic neurons (Fig. 8F). At e6.5, expression of Cyp26C1 is still present within the roof plate (Fig. 8G) but down-regulated in dividing neural precursors. In the hindbrain, expression is found in three discrete nuclear clusters (Fig. 8H). Transverse sections show that expression of Cyp26C1 in the roofplate does not spread to the meninges (Fig. 8I) and that labelled hindbrain nuclei form a contiguous column (Fig. 8K–L) which correspond with higher levels of RXRγ (Fig. 5J).

Bottom Line: Intriguingly, transcripts of cellular retinoic acid binding protein 1 are always found at the interface between dividing and post-mitotic cells.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: MRC Centre for Developmental Neurobiology, King's College London, 4th floor New Hunt's House, Guy's Campus, London SE1 1UL, UK. leigh.wilson@kcl.ac.uk

ABSTRACT

Background: 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.

Results: 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.

Conclusion: 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.

Show MeSH
Related in: MedlinePlus