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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.

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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 Cyp26A1. A. Dorsal view of Cyp26A1 expression in the rhombic lip at e3.5. B. Dorsal view of Cyp26A1 expression in the rhombic lip and roofplate (*) at e5. C. Transverse section through an e3.5 hindbrain (dashed line in A) showing Cyp26A1 expression at the rhombic lip (arrow) D. Transverse section through an e5 hindbrain (dashed line in B), showing punctate expression of Cyp26A1 extending into the roofplate (arrow). E. Ventral view of the hindbrain at e5 shows Cyp26A1 within a discrete population of neurons. F. Tlx3 expression at e5 identifies the noradrenergic area postrema (arrow). G. In section (dashed line in F), the area postrema (arrow) overlies the nucleus ambiguus (white arrow). H. Transverse section through caudal hindbrain (dashed line in E) shows Cyp26A1 expression approximately mapping to neurons that express Tlx3 (arrow). I. Ventral view of hindbrain at e6 shows columnar Cyp26A1 expression. J and K. Transverse sections through rostral and caudal parts of the hindbrain expression domain (dashed black and white lines in I), respectively. L. Lateral view of e6 embryo showing relative positions of hindbrain and midbrain label (arrow). M. Dorsal view of e8 embryo; discrete expression at the caudal margin of the optic tectum (arrow). N. Transverse section through midbrain expression domains (dashed line in M).
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Figure 6: Expression of Cyp26A1. A. Dorsal view of Cyp26A1 expression in the rhombic lip at e3.5. B. Dorsal view of Cyp26A1 expression in the rhombic lip and roofplate (*) at e5. C. Transverse section through an e3.5 hindbrain (dashed line in A) showing Cyp26A1 expression at the rhombic lip (arrow) D. Transverse section through an e5 hindbrain (dashed line in B), showing punctate expression of Cyp26A1 extending into the roofplate (arrow). E. Ventral view of the hindbrain at e5 shows Cyp26A1 within a discrete population of neurons. F. Tlx3 expression at e5 identifies the noradrenergic area postrema (arrow). G. In section (dashed line in F), the area postrema (arrow) overlies the nucleus ambiguus (white arrow). H. Transverse section through caudal hindbrain (dashed line in E) shows Cyp26A1 expression approximately mapping to neurons that express Tlx3 (arrow). I. Ventral view of hindbrain at e6 shows columnar Cyp26A1 expression. J and K. Transverse sections through rostral and caudal parts of the hindbrain expression domain (dashed black and white lines in I), respectively. L. Lateral view of e6 embryo showing relative positions of hindbrain and midbrain label (arrow). M. Dorsal view of e8 embryo; discrete expression at the caudal margin of the optic tectum (arrow). N. Transverse section through midbrain expression domains (dashed line in M).

Mentions: Cyp26A1 is expressed exclusively at the rhombic lip at e3.5 (Fig. 6A). At e5, punctate Cyp26A1 expression is also found in the roofplate into the fourth ventricle (Fig. 6B). The expansion of the Cyp26A1 expression domain can be seen in transverse section (compare Fig. 6C and 6D). Cyp26A1 also becomes upregulated in a caudal hindbrain nucleus close to the ventral midline (Fig. 6E). At this stage, Tlx3, identifies noradrenergic-specific cells in the caudal hindbrain [47] (Fig. 6F). In transverse section, Tlx3 characterises a band of neurons located close to the ventricular surface in the area postrema and a deeper column of neurons presumably corresponding to the noradrenergic component of the nucleus ambiguus (Fig. 6G). This latter population also expresses Cyp26A1 (Fig. 6H). At e6, Cyp26A1 expression is down-regulated in the rhombic lip and roof plate. Within the caudal hindbrain (Fig. 6I), a narrow rostral extension of Cyp26A1 (Fig. 6J) abuts the domain corresponding to that at e5 (Fig. 6K). Cyp26A1 expression can also be detected at e6 within the midbrain (Fig. 6L). Labelled neurons lie at the caudal seam of the optic tectum (Fig. 6M) in a superficial location approximating to the position of the isthmo-optic nucleus (Fig. 6N).


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 Cyp26A1. A. Dorsal view of Cyp26A1 expression in the rhombic lip at e3.5. B. Dorsal view of Cyp26A1 expression in the rhombic lip and roofplate (*) at e5. C. Transverse section through an e3.5 hindbrain (dashed line in A) showing Cyp26A1 expression at the rhombic lip (arrow) D. Transverse section through an e5 hindbrain (dashed line in B), showing punctate expression of Cyp26A1 extending into the roofplate (arrow). E. Ventral view of the hindbrain at e5 shows Cyp26A1 within a discrete population of neurons. F. Tlx3 expression at e5 identifies the noradrenergic area postrema (arrow). G. In section (dashed line in F), the area postrema (arrow) overlies the nucleus ambiguus (white arrow). H. Transverse section through caudal hindbrain (dashed line in E) shows Cyp26A1 expression approximately mapping to neurons that express Tlx3 (arrow). I. Ventral view of hindbrain at e6 shows columnar Cyp26A1 expression. J and K. Transverse sections through rostral and caudal parts of the hindbrain expression domain (dashed black and white lines in I), respectively. L. Lateral view of e6 embryo showing relative positions of hindbrain and midbrain label (arrow). M. Dorsal view of e8 embryo; discrete expression at the caudal margin of the optic tectum (arrow). N. Transverse section through midbrain expression domains (dashed line in M).
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Figure 6: Expression of Cyp26A1. A. Dorsal view of Cyp26A1 expression in the rhombic lip at e3.5. B. Dorsal view of Cyp26A1 expression in the rhombic lip and roofplate (*) at e5. C. Transverse section through an e3.5 hindbrain (dashed line in A) showing Cyp26A1 expression at the rhombic lip (arrow) D. Transverse section through an e5 hindbrain (dashed line in B), showing punctate expression of Cyp26A1 extending into the roofplate (arrow). E. Ventral view of the hindbrain at e5 shows Cyp26A1 within a discrete population of neurons. F. Tlx3 expression at e5 identifies the noradrenergic area postrema (arrow). G. In section (dashed line in F), the area postrema (arrow) overlies the nucleus ambiguus (white arrow). H. Transverse section through caudal hindbrain (dashed line in E) shows Cyp26A1 expression approximately mapping to neurons that express Tlx3 (arrow). I. Ventral view of hindbrain at e6 shows columnar Cyp26A1 expression. J and K. Transverse sections through rostral and caudal parts of the hindbrain expression domain (dashed black and white lines in I), respectively. L. Lateral view of e6 embryo showing relative positions of hindbrain and midbrain label (arrow). M. Dorsal view of e8 embryo; discrete expression at the caudal margin of the optic tectum (arrow). N. Transverse section through midbrain expression domains (dashed line in M).
Mentions: Cyp26A1 is expressed exclusively at the rhombic lip at e3.5 (Fig. 6A). At e5, punctate Cyp26A1 expression is also found in the roofplate into the fourth ventricle (Fig. 6B). The expansion of the Cyp26A1 expression domain can be seen in transverse section (compare Fig. 6C and 6D). Cyp26A1 also becomes upregulated in a caudal hindbrain nucleus close to the ventral midline (Fig. 6E). At this stage, Tlx3, identifies noradrenergic-specific cells in the caudal hindbrain [47] (Fig. 6F). In transverse section, Tlx3 characterises a band of neurons located close to the ventricular surface in the area postrema and a deeper column of neurons presumably corresponding to the noradrenergic component of the nucleus ambiguus (Fig. 6G). This latter population also expresses Cyp26A1 (Fig. 6H). At e6, Cyp26A1 expression is down-regulated in the rhombic lip and roof plate. Within the caudal hindbrain (Fig. 6I), a narrow rostral extension of Cyp26A1 (Fig. 6J) abuts the domain corresponding to that at e5 (Fig. 6K). Cyp26A1 expression can also be detected at e6 within the midbrain (Fig. 6L). Labelled neurons lie at the caudal seam of the optic tectum (Fig. 6M) in a superficial location approximating to the position of the isthmo-optic nucleus (Fig. 6N).

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