A tale of tailless

Abstract

Drosophila Tailless(Tll) and its vertebrate homologue Tlx are conserved orphan nuclear receptors specifically expressed in the eye and the forebrain. Tll and Tlx act primarily as transcriptional repressors through their interactions with transcriptional corepressors, Atrophin family proteins, and histone-tail/chromatin-modifying factors such as lysine-specific histone demethylase 1 and histone deacetylases. The functional importance of Tll and Tlx is made apparent by the recent discovery that they are expressed in neural stem cells (NSCs) and are required for self-renewal of these cells in both Drosophila and the mouse. This review provides a snapshot of current knowledge about Tll and Tlx and their transcriptional network, which maintains NSCs in developing and adult animals.

Fig. 1

tll is expressed at the terminal regions in early embryos and in undifferentiated neural precursors in tissues at the third instar larval stage. In situ hybridization experiments were performed on stage 4–5 embryos (a), on optic lobes (b), and on antenna/eye imaginal disks (c) isolated from third-instar larvae, using digoxigenin-labeled anti-tll RNA probes. The enlarged image shown in b represents a lateral view of the optic lobe (OL) where tll is specifically expressed in two crescent-shaped clusters of proliferating NBs. d A schematic diagram showing the role of Tll in specifying optic lobe cell fate. Founder cells secrete a ligand of EGFR, called ‘Spitz’, which binds EGFR located on the surface of the nearby primordial cells, which have the capacity to become either optic lobe or Bolwig's organ (light-sensing larval eye) cells. By antagonizing EGFR signaling, Tll directs primordial cells to adopt the optic lobe cell fate. Those primordial cells that lack Tll, in response to the activated EGFR signaling, become Bolwig's organ. VNC = Ventral nerve cord; MF = morphogenetic furrow.

Fig. 2

Comparison between Tll, Tlx, and other NR2 class of nuclear receptors. (a) Tll and Tlx are members of the nuclear receptor superfamily. Common features of nuclear receptors include DNA-binding domains (DBD) and ligand-binding domains (LBD). Interactions with corepressors, such as atrophin family proteins, are mediated through the ligand-binding domain, while association with LSD1 is mediated through both the DNA-binding and the ligand-binding domains. b Alignments of multiple sequences corresponding to the DNA-binding domain of Tailless proteins and other NR2E and NR2F subclasses proteins. P, D and T/A boxes are involved in DNA binding and dimerization. c Phylogenetic tree showing the relationship among Tailless, Tlx, and other NR2 family proteins across species using the maximum-parsimony method. The bootstrap consensus tree inferred from 1,000 replicates is taken to represent the evolutionary history of the taxa analyzed. The maximum-parsimony tree was obtained using the Close-Neighbor-Interchange algorithm with a search level of 5, in which the initial trees were obtained with the random addition of sequences (10 replicates). The tree is drawn to scale, with branch lengths calculated using the average-pathway method and are expressed in terms of the number of changes over the whole sequence. Phylogenetic analyses were conducted in MEGA4 [90]. Mu = Mouse; Hu = human.

Fig. 3

Tlx maintains NSC self-renewal at all stages in the mouse brain. The upper diagram in each panel shows the expression pattern of Tlx in the mouse brain at the indicated stage; the lower diagram in each panel is an enlarged view of the ventricular region where Tlx is expressed. a At the embryonic stage, Tlx forms a graded pattern in the telencephalon along the dorsal-ventral axis. Its expression level is high in the dorsal-lateral region, but is low in the ventral-medial region. Its expression in NSCs in the VZ prevents them from undergoing premature neurogenesis and losing self-renewal ability. NSCs at the early stage generate deep-layer cortical neurons by asymmetrical division and later make a transition to Tbr2-positive basal progenitors (BP, marked with yellow nucleus) in the SVZ, which give rise to upper-layer neurons (marked with red nucleus). NSCs that are Tlx positive (Tlx+) are marked with blue in their nuclei, and nestin-positive (nestin+) cells are marked with magenta in their cytoplasm. b At the postnatal stage, Tlx is expressed in the VZ and is essential for radial glia (RG) to become astrocyte-like B cells, which are the source of adult NSCs. Induced mutation of Tlx at this stage causes loss of adult NSCs or decreased proliferative ability. Radial glia at this stage (Tlx+/nestin+) are pluripotent, giving rise to neurons, oligodendrocytes and astrocytes. c During adult stages, Tlx is also found in astrocyte-like B cells (GFAP+) at the subependymal zone of the adult CNS. Mutation of Tlx causes complete loss of the self-renewal ability of adult NSCs. LGE = Lateral ganglionic eminence; MGE = medial ganglionic eminence.

Fig. 4

Tlx enables NSCs to undergo self-renewal by repressing the expression of Pten, prospero/Prox1, or Cip/Kip family members such as p21 and p57. Both Pten and p21 function to inhibit G₀→G₁ entry and G₁/S progression. Their increased expression in Tlx mutant cells leads to the inhibition of proliferation and self-renewal of stem cells. The ability of Tll or Tlx to repress the expression of its target genes depends on inputs from the atrophin (Atro) proteins, HDACs, or LSD1.