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First published online 11 February 2004
doi: 10.1242/dev.01029

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Contribution of Hox genes to the diversity of the hindbrain sensory system

Howard Hughes Medical Institute, Department of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA

View larger version (87K): [in a new window]   Fig. 1. Characterization of noradrenergic interneuron precursors in the caudal hindbrain. Hindbrain flat-mount preparations of E11.5 control embryos showing the mRNA expression of (A) Dbh, (B) Rnx, (C) Phox2b and (D) Mash1. The box outlines the domain that gives rise to noradrenergic visceral sensory interneurons of the solitary tract nucleus (STN). LC, locus ceruleus; FBMN, facial branchiomotoneurons.

View larger version (56K): [in a new window]   Fig. 2. Hoxb1 regulates early differentiation of noradrenergic visceral sensory interneurons in r4. (A-D) Hindbrain flat-mount preparations showing Dbh and Rnx expression are missing in dorsal r4 of E11.5 Hoxb1-/- embryos compared with control littermates. (E,F) Expression of Phox2b mRNA is significantly reduced in dorsal r4 of E10.5 (insets) and E11.5 Hoxb1-/- embryos compared with control littermates.

View larger version (78K): [in a new window]   Fig. 3. Distinct combination of Hox genes is required for Mash1-dependent Phox2b protein expression in r4 and r5. Transverse sections through r4 and r5 of E10.5 control (A,E), Hoxb1-/- (B,F), Hoxa3-/-b3-/- double (C,G) and Mash1-/- (D,H) embryos. The expression of Phox2b among precursors of noradrenergic visceral interneurons is missing (compare with arrows in A,C,E,F) in dorsal r4 of Hoxb1-/- and dorsal r5 of Hoxa3-/-b3-/- embryos compared with controls. In the Mash1-/- embryo, Phox2b expression is completely eliminated in the dorsal region of r4 and r5. VII/VIIIg, ganglia; OV, otic vesicle.

View larger version (87K): [in a new window]   Fig. 4. Loss of precursors of noradrenergic visceral sensory interneurons is associated with the expansion of neighboring interneurons in r5 and r4. Transverse sections through r5 and r4 of E11.5 control (A,C), Hoxa3-/-b3-/- (B) and Hoxb1-/- (D) embryos. The co-expression (yellow) of Phox2b (green) and Lmx1b (red) among noradrenergic precursors is eliminated in the dorsal hindbrain of Hoxa3-/-b3-/- and Hoxb1-/- embryos. The intermediate column of Phox2b and the more ventral population of Lmx1b-expressing cells appear unaffected in the Hox mutant embryos. The domain of Lim1/2 (blue, bracket) expression has expanded in both Hox mutant embryos compared with controls. Comparison of transverse sections at comparable DV axial levels through r3 of an E11.5 control embryo (E-G) with r5 and r4 Hoxa3-/-b3-/- and Hoxb1-/- mutant embryos (B,D) show similar expression patterns of Phox2b, Lmx1b and Lim1/2.

View larger version (54K): [in a new window]   Fig. 5. Regulation of proprioceptive and somatic sensory interneurons is independent of Hoxb1, Hoxa3 and Hoxb3 functions in r4 and r5. Expression of LH2A/B (green, arrow) and Lim1/2 (red) in r4 and r5 of controls (A,C) compared with Hoxb1-/- (B) and Hoxa3-/-b3-/- (D) embryos. Lim1/2 expression is expanded in both Hox mutant embryos compared with their controls. Expression of Lbx1 (green) and Lim1/2 (red) in E11 control (E) and Hoxb1-/- (F) embryos and E11.5 control (G) and Hoxa3-/-b3-/- (H) embryos is intact. The co-expression of Lim1/2 and Lbx1 suggests that the Lbx1 population is also expanded in Hox mutant embryos compared with controls (bracket).

View larger version (77K): [in a new window]   Fig. 6. Differential regulation of precursors for proprioceptive and somatic sensory interneurons in r2. Expression of LH2A/B is intact in r2 of E11.5 control (A) and Hoxa2-/- (B) embryos. Labeling of Lbx1 in r2 of E11.5 control (C) and Hoxa2-/- (D) embryos shows complete loss of Lbx1 expression in the Hoxa2-/- embryo. The trigeminal branchiomotoneurons (box), co-labeled with Phox2b (green) and Isl1/2 (red), are intact in the Hoxa2-/- embryo compared with the littermate control (E,F). Lbx1 expression in r3 of E11.5 control (G) and Hoxa2-/- (H) embryos shows a significant reduction in the Hoxa2-/- embryo.

View larger version (33K): [in a new window]   Fig. 7. Summary. (A) Schematic view of a flat-mount hindbrain showing Hox gene expression on the left (bars) and first-order visceral (noradrenergic), somatic and proprioceptive sensory relay interneurons (circles) on the right. The loss of Hoxb1 (B) and the combination of Hoxa3 and Hoxb3 (C) result in a specific loss of visceral interneurons in r4 and r5, respectively. The loss of visceral sensory interneurons in these Hox mutant embryos is associated with the expansion of the somatic sensory interneuron domain. In Hoxa2 loss-of-function (D), somatic sensory interneurons are completely eliminated in r2 and significantly reduced in r3, presumably through the redundant role of Hoxb2 in this rhombomere (see A). Although Hox genes are expressed throughout the early neuroepithelium, the present finding suggests a specific role for Hox genes in the generation of cellular diversity in the developing hindbrain.