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The vertebrate forebrain is formed at the rostral end of the neural plate under the regulation of local and specific signals emanating from both the endomesoderm and neuroectoderm. The development of the rostral and ventralforebrain in particular was difficult to study, mainly because no specific markers are available to date. Here, we report the identification of Vax1, a novel homeobox-containing gene identified in mouse, Xenopus and human. It is closely related to members of the Not and Emx gene families, all of which are required for the formation of structures where they are expressed. In mouse and Xenopus, Vax1 expression first occurs in the rostral neural plate, in the medialanterior neural ridge and adjacent ectoderm. Later, at midgestation in the mouse and tadpole stage in Xenopus, the expression remains confined in the derivatives of this territory which differentiate into rostromedial olfactory placode, optic nerve and disc, and anteriorventralforebrain. Together, these observations suggest that Vax1 could have an early evolutionary origin and could participate in the specification and formation of the rostral and ventralforebrain in vertebrates. Comparison of the limits of the expression territory of Vax1 with that of Dlx1, Pax6 and Emx1 indicates that the corticostriatal ridge is a complex structure with distinct identifiable genetic compartments. Besides, the study of Vax1 expression in Pax6-deficient homozygous brains indicates that its regulation is independent of Pax6, although the expression patterns of these two genes appear complementary in wild-type animals. Vax1 chromosomal location is mapped at the distal end of the mouse chromosome 19, linked with that of Emx2. These two genes may have arisen by tandem duplication. The Vax1 gene is thus an interesting new tool to study the rostral ventralforebrain patterning, morphogenesis and evolution as well as the terminal differentiation of the forebrain in mouse and Xenopus.
Fig. 5. Expression of XVax1 during early development (stages as
indicated, A) and in tissues of adult frogs (B) as detected by
quantitative RT-PCR. Transcription of Xvax1 is activated in early
gastrula and upregulated during neurulation. te, testis; ov, ovary; sc,
spinal cord; br, brain; ey, eye; fa, fat body; bl, bladder; lu, lung; ki,
kidney; li, liver; sp, spleen; in, intestine; st, stomach; gu, gut; mu,
muscle; he, heart; sk, skin.
Fig. 6. Developmental expression of XVax1 analyzed by wholemount
in situ hybridization. (A) Anterior view of an embryo at stage
16. Staining is detected in the anterior neural ridge. (B) Anterior
view of XVax1 expression at stage 19. XVax1 signal is visible in the
ventralforebrain. The optic vesicle (OV) shows no expression.
(C) Ventral/anterior view of an embryo at stage 26. XVax1 transcripts
are detected in the ventralhypothalamus (vh), optic stalk (OS) and
the optic disc (OD). (D) Lateral view at stage 34. XVax1 transcripts
are located the ventral and anteriorforebrain. (E) To improve
resolution, a cleared embryo at stage 34 is shown in a dorsal/lateral
view. Strong XVax1 expression is visible in the ventralanteriorforebrain with a sharp dorsal boarder. (F-H) Sections of stained
plastic embedded embryos at stage 34. F; In a sagittal section XVax1
transcripts are detected in the chiasmatic ridge and the ventralhypothalamus. (G) Parasagittal section showing XVax1 expression in
the eye disc and in the optic stalk. (H) Transverse section at the level
of the optic chiasm. ar, anteriorridge; ba, branchial arch; Ch,
chiasmatic ridge; di, diencephalon; fbv, forebrain vesicle; gu, gut; i,
infundibulum; nc, notochord; OD, optic disk; OS, optic stalk; OV,
optic vesicle; sep, septal/striatal region; vh, ventralhypothalamus;
vtt, ventral tegmental tract.
Fig. 1. (A) Vax1 mouse and Xenopus amino acid sequence comparison. GenBank accession
numbers for Vax1 sequences are AF064554 and AF064601. (B) Mouse and Xenopus Vax1
homeodomain amino acid sequence alignment in comparison to the homeodomain of
Drosophila (dm) ems, Homo sapiens (hs), mouse (mm) Emx1 and Emx2, Xenopus (xl) and
chicken (gg) Not1. Identical amino acids are represented by hyphens. Dots represent gaps
introduced in the amino acid sequence in order to obtain optimal alignment. Identity (ID)
values were calculated pairwise. The human and mouse Emx homeobox amino acid sequences
are identical. Only the mouse sequences are thus presented. The underlined amino acid of the
mouse Vax1 sequence indicate the predicted positions of the three helixes of the homeodomain.
The intron sequence between position 44 (Q) and 45 (V) within the third helix of the homeobox
of the human EST clone sequence has been removed from the sequence in this figure.
Fig. 2. Vax1 is mapped in the distal region of mouse chromosome 19.
(A) Vax1 was placed on mouse chromosome 19 by interspecific
backcross analysis. The segregation patterns of Vax1 and flanking
genes in 113 backcross animals that were typed for all loci are shown
at the top of the figure. For an individual pair of loci, more than 113
animal were typed (see text). Each column represents the
chromosome identified in the backcross progeny that was inherited
from the (C57BL/6J × M. spretus) F1 parent. The shaded boxes
represent the presence of a C57BL/6J allele and white boxes
represent the presence of a M. spretus allele. The number of
offspring inheriting each type of chromosome is listed at the bottom
of each column. (B) A partial chromosome 19 linkage map showing
the location of Vax1 in relation to linked genes. Recombination
distances between loci in centimorgans are shown to the left of the
chromosome and the positions of the loci in human chromosomes,
where known, are shown to the right. References for the human map
positions of loci cited in this study can be obtained from GDB
(Genome DataBase), a computerized database of human linkage
information maintained by the William H. Welsh Medical Library of
The John Hopkins University (Baltimore, MD).
vax1 (ventral anterior homeobox 1) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 16, anterior view, dorsal up.
vax1 (ventral anterior homeobox 1) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 34, lateral view, anteriorleft, dorsal up.
