Sena E et al. (2016), An Evolutionarily Conserved Network Mediates De...

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J Dev Biol 2016 Oct 20;44:. doi: 10.3390/jdb4040031.

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An Evolutionarily Conserved Network Mediates Development of the zona limitans intrathalamica, a Sonic Hedgehog-Secreting Caudal Forebrain Signaling Center.

Sena E , Feistel K , Durand BC .

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Recent studies revealed new insights into the development of a unique caudal forebrain-signaling center: the zona limitans intrathalamica (zli). The zli is the last brain signaling center to form and the first forebrain compartment to be established. It is the only part of the dorsal neural tube expressing the morphogen Sonic Hedgehog (Shh) whose activity participates in the survival, growth and patterning of neuronal progenitor subpopulations within the thalamic complex. Here, we review the gene regulatory network of transcription factors and cis-regulatory elements that underlies formation of a shh-expressing delimitated domain in the anterior brain. We discuss evidence that this network predates the origin of chordates. We highlight the contribution of Shh, Wnt and Notch signaling to zli development and discuss implications for the fact that the morphogen Shh relies on primary cilia for signal transduction. The network that underlies zli development also contributes to thalamus induction, and to its patterning once the zli has been set up. We present an overview of the brain malformations possibly associated with developmental defects in this gene regulatory network (GRN).

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Species referenced: Xenopus
Genes referenced: barhl2 fezf2 gli3 irx1 irx2 irx3 notch1 otx1 otx2 pax6 shh tead1 tub wnt3a yap1

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	Figure 1. Schematic of Xenopus (X.) laevis forebrain markers and flat-mounted neural tubes from X. laevis and Mus musculus embryo after whole-mount double in situ-hybridization (WM-dISH). (A) Schematic of X. laevis forebrain markers at st. 30. (a) Areas of expression are shown and indicated for fezf2 (pink), pax6 (checkerboard pattern), irx3 (yellow), wnt3a (light green), shh (orange), barhl2 (hatched lines), and irx1 (red). (b) Enlargement of the diencephalic part indicated by a rectangle in (a). The pineal gland located on top of p2 is marked by an asterisk. The future zli is indicated in (b). p: prosomere; Tel: telencephalon; Mes: mesencephalon; Pre-Th: pre-thalamus; zli: zona limitans intrathalamica; Th: thalamus. (B) WM-dISH is performed using otx2, irx1, irx3, fezf2, pax6, and shh or barhl2 as probes on (a–g). X. laevis and mouse embryos at different developmental stages as indicated. Neural tubes (a–f) or heads (h,i) of representative embryos, dissected and flat-mounted, are shown from a side view, dorsal up, anterior left except for (g), shown in anterior view, dorsal side up. The markers and stages are indicated. Black arrows indicate the rostral and caudal boundaries of p2. White arrows indicate the bilateral zli. Scale bar: 0.5 mm.
	Figure 2. A model for zli formation. (A) During neural plate patterning the diencephalic primordium expresses otx2, barhl2 and irx1, irx2, irx3 (orange). Cross-repressive interactions between Fezf/Fez and Irx homeoproteins contribute to formation of the p2/p3 alar border. shh (light blue) is expressed in the p2 basal plate. (B) Concomitantly, a Wnt-mediated signal promotes survival of zli anlage cells, and gli3 expression is repressed through a Wnt-mediated signal in a narrow band of cells that correspond to the zli primordium. (C) At the onset of zli formation a permissive environment is established in the future zli, and zli cells acquire the competence to express shh. The zli anlage is characterized by the expression of barhl2, otx2, irx3 (orange), and the future thalamus by the expression of barhl2, otx2, irx1/2/3 (green). At the onset of zli development, irx3 is expressed in the future thalamus territory. (D) Using a sequential induction mechanism, Shh secreted by the basal plate initiates the spreading of shh expression into the pre-zli domain. Transcription factors (TFs) including Otx1, Otx2, Barhl2, Yap–Tead, and possibly unidentified TFs (TF-X) are recruited to the enhancers SBE1 and SBE5 to initiate shh transcription within the zli. Under the inductive influence of secreted N-Shh, some irx3-expressing cells located in caudal p2 sort out from thalamic cells. Shh signaling from the zli induces the repression of pax6 within the mid-diencephalic furrow. Pax6 together with unidentified dorsal signals could in turn prevent Shh from being expressed beyond the zli. The thalamus (p2) and the prethalamus (p3) receive a combination of Shh signals coming from two orthogonally oriented signaling centers, the zli and the basal plate. Together, they establish a morphogenetic gradient of Shh protein that patterns the thalamus posterior to the zli and the prethalamus anterior to the zli. p: prosomere; zli: zona limitans intrathalamica.
	Figure 3. Elongated cilia on the zli. (A) Schematic overview of the Xenopus tadpole brain comprised of (from anterior to posterior) telencephalon (tel), diencephalon (di), mesencephalon (mes) and rhombencephalon (rhomb). The position of the zli is indicated by orange dashed line. (B) Magnification of area indicated by white dashed line in (A). Whole mount immunofluorescence staining on the ventricular surface of a tadpole brain. Antibodies detecting acetylated alpha-tubulin (ac. α-tub.) and gamma-tubulin (γ-tub.) mark cilia axonemes and basal bodies, respectively. Note that zli cilia are markedly elongated compared to cilia on neighboring cells (scale bars: 5 µm).

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Acampora, The role of Otx and Otp genes in brain development. 2000, Pubmed