Morona R et al. (2025), Developmental and adult expression of the Meis2...

XB-ART-61606

Front Neuroanat 2025 Nov 06;19:1677413. doi: 10.3389/fnana.2025.1677413.

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Developmental and adult expression of the Meis2 transcription factor in the central nervous system of Xenopus laevis: a developmental and evolutive analysis.

Morona R , Martinez A , Moreno N .

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Myeloid ecotropic viral integration site 2 (Meis2) is a three-amino-acid-loop-extension (TALE) transcription factor (TF) involved in key neurodevelopmental processes, such as neuronal differentiation and brain regionalization. Its expression is well documented in amniotes and teleosts, but its distribution in the developing brain of anamniote tetrapods remains poorly understood. Therefore, the distribution of Meis2-immunoreactive (-ir) cells was analyzed throughout the developmental stages of the Xenopus laevis brain, revealing a dynamic, stage-specific expression pattern. From the early embryonic stages, Meis2-ir cells were found in the telencephalon, specifically in the ventrolateral pallium and subpallium; the diencephalon, particularly in the prosomere 3 and transiently in p2 and in the habenula; the optic tectum; the mesencephalic tegmentum; and the rhombencephalon. During the premetamorphic stages, Meis2 expression extended rostrally in the olfactory bulb (OB) and to subpallial derivatives, including scattered cells in the amygdaloid region. It was present in the alar and basal hypothalamus. During the metamorphic climax and juvenile phases, Meis2-ir expression became clearly defined in specific mature nuclei, specifically in the ventral pallium, the bed nucleus of the stria terminalis, septal nuclei, supra-paraventricular and mammillary hypothalamus, and prethalamic nuclei. In addition, from the metamorphic climax stages, Meis2 occupied a number of tectal layers and was observed in the cerebellar nucleus. The most prominent and constant expression was observed in the rhombencephalon, particularly in areas surrounding the isthmus and the reticular formation. This expression extended from rostral rhombomeres (r1-r3) caudally into the lateral line system and raphe nuclei. These results highlight the conserved and temporally regulated role of Meis2 in the regional specification and maturation of the central nervous system and reveal particularities related to cell specification.

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	Figure 1. (a) Representation of the structure and main domains of the human Meis2, Meis1, and Meis3 proteins. The domains are labeled in Meis2 and the color code is maintained in Meis1 and Meis3. (b) The 3D structure obtained from the AlphaFold Protein Structure Database and PDBe-KB (Protein DATA Bank in Europe Knowledge Base) for human Meis2 Uniprot Id: O14770.2 Entrez Gene ID: 4212. The central part, including the homeodomain (cyan rectangle) and the Nt loop, contains the antigenic sequence recognized by the antibody used (violet rectangle). (c) Alignment of the Meis1, Meis2, and Meis3 orthologs between Homo sapiens and Xenopus laevis. (d) Percentage of homology with the amino acid sequence of the antigenic epitope for the Meis1, Meis2, and Meis3 orthologs in Xenopus laevis and Homo sapiens. (e) Western blot analyses of brain extracts from Xenopus (X.l), dilution of the purified Meis2 human protein (H.s), and Rattus norvegicus (R.n), stained with the mouse anti Meis2 antibody. Standard molecular weight (MW) is represented on the left side of the photograph.
	Figure 2. Phylogenetic tree illustrating the relationships among the amino acid sequences of the transcription factor Meis2 in the indicated animal models based on a COBALT multiple alignment of the human Meis2 orthologs, as defined by the NCBI orthologs criteria. The accession number of each ortholog is provided under the species name in the diagram. The scale bar represents distance, and the percentage of calculated homology with human Meis2 (Uniprot Id: O14770.2) is shown in each terminal branch. Free images were obtained from BioRender or Adobe Stock and modified using CANVAS.
	Figure 3. Photomicrographs of Meis2-ir transverse (a–t) and sagittal (u–x) sections at representative brain levels of Xenopus during embryonic stages. Topological dorsal and rostral orientations are indicated by rows, with respect to the alar-basal boundary (ABB). Stages 37–38 (a–g), 42 (h–n), and 46 (o–q) are indicated on each photomicrograph. The approximate levels of transverse sections are indicated in (u). Dashed lines mark the approximate boundary between neuromeres and telencephalic subdivisions. See the list for abbreviations. Scale bars = a–n =50 μm, p–t, v–x = 100 μm = 200 μm.
	Figure 4. Photomicrographs of double-labeled transverse (a–d, g–j, n–p) and sagittal (e, f, k–m, q) sections at representative brain levels of Xenopus from stages 42 to 50. Topological dorsal and rostral orientations are indicated by rows, with respect to the alar-basal boundary (ABB), indicated by a rough dashed line in sagittal sections. Color codes for the markers are indicated in the upper left corner of each photo. Thin dashed lines represent the approximate boundaries within telencephalic, diencephalic, mesencephalic, and rhombencephalic subdivisions. See the list for abbreviations. Scale bar p–x = 100 μm, u = 200 μm, others = 50 μm.
	Figure 5. Photomicrographs of double-labeled transverse (a–d, h–n) and sagittal (e–g) sections at representative brain levels of Xenopus from stages 53–56. Topological dorsal and rostral orientations are indicated by rows, with respect to the alar-basal boundary (ABB), indicated by a rough dashed line in sagittal sections. In all photographs, green is Meis2ir, red is Otp, and blue is DAPI staining. Thin dashed lines represent the approximate boundaries within telencephalic, diencephalic, mesencephalic, and rhombencephalic subdivisions. See the list for abbreviations. Scale bar, all = 100 μm.
	Figure 6. Schematic diagrams showing the rostrocaudal distribution of Meis-2ir in the adult brain. In all diagrams, dorsal is oriented upward. The main subdivisions are indicated by dashed lines. The approximate levels are indicated in the upper sagittal scheme. See the list for abbreviations.
	Figure 7. Photomicrographs of double-labeled transverse (a–c, e, f, i–m) and sagittal (d, g, h) sections at representative brain levels of Xenopus from stages 53–56. Topological dorsal and rostral orientations are indicated by rows, with respect to the alar-basal boundary (ABB), indicated by a rough dashed line in sagittal sections. Color codes for the markers are indicated in the upper left corner of each photo. Thin dashed lines represent the approximate boundaries within telencephalic, diencephalic, mesencephalic, and rhombencephalic subdivisions. See the list for abbreviations. Scale bar, all = 100 μm.
	Figure 8. Photomicrographs of double-labeled transverse (a–c, e, f, i–m) and sagittal (d, g, h) sections at representative brain levels of Xenopus from stages 53–56. Image (h) is a magnification of (j) at the level of the laterodorsal nucleus. (i) is a magnification of the locus ceruleus in (l). Images (n) and (o) are magnifications of (m) at the reticular formation and DCN respectively. Topological dorsal and rostral orientations are indicated by rows. The alar-basal boundary (ABB) is indicated by a rough dashed line in sagittal sections. Color codes for the markers are indicated in the upper left corner of each photo. Thin dashed lines represent the boundaries within telencephalic, diencephalic, mesencephalic, and rhombencephalic subdivisions. See the list for abbreviations. Scale bar, no = 25 μm, rest = 100 μm.
	Figure 9. (a) Sagittal schematic diagrams representing the distribution of Meis1 (blue), (b) Meis2 (green), and Meis3 (dark green lines) in the mouse postnatal brain (Allen brain), compared to the distribution of Meis2-ir in the Xenopus brain (c). In all diagrams, dorsal is oriented upward and rostral is oriented to the left. The main subdivisions are indicated by thin lines. See the list for abbreviations.
	Figure 10. Timeline of the appearance of Meis2 cell groups in the developing brain of Xenopus laevis.