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First published online February 2, 2004
doi: 10.1242/10.1242/dev.01043

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Morphogens, their identification and regulation

Institute of Molecular and Cellular Biosciences, University of Tokyo, Yayoi 1-1-1, Bunkyo-ku, Tokyo 113-0032, Japan

View larger version (51K): [in a new window]   Fig. 1. Mirror image duplication can be induced by an ectopic source of the morphogen molecule. (A) A model for morphogen signaling. A morphogen emanating from the expressing cell (S) sets the positional value of a cell by forming a concentration gradient across the developmental field in which the cell resides; the value of the gradient at each point in the field is a function of the distance of the receiving cell from the morphogen-secreting cells (left). Introduction of an ectopic source (S') of morphogen can induce mirror image duplication (underline; right). (B) Wing imaginal disc (red) of third instar Drosophila larva. The imaginal disc is a two-sided sac comprising a columnar cell layer that contains presumptive wing blade (wb) and thorax (t) regions, and an overlying squamous peripodial membrane (pm); it is set aside from the embryonic epidermis and develops at the larval stage. The imaginal disc is subdivided into anterior (A) and posterior (P) compartments along the anteroposterior axis. hedgehog (hh) is expressed in the posterior compartment; hh mRNA is visualized with in situ hybridization (left). Schematic on right modified with permission from Bryant and Levinson (Bryant and Levinson, 1985). (C) Ectopic expression of hh, by making a clone of cells expressing hh, induces a mirror image duplication of the anterior wing structure. Hh produced in the P compartment is secreted into the A compartment (top). A clone of cells ectopically expressing hh in the A compartment induces a complete mirror image duplication of the A compartment (bottom). Wing veins I V are indicated. Reproduced with permission from Tabata (Tabata, 2001). (D) Ectopic production of Shh, induced by implanting shh-expressing cells into the anterior limb bud, induces a mirror image duplication of the wing structure. shh is expressed in the region corresponding to the ZPA in the wing bud (top). Implanted cells that ectopically produce Shh in the anterior of the limb bud induce a mirror image duplication of the wing structure (bottom). Digits (II, III and IV) are labeled on the schematic, and radius (R), ulna (U) and humerus (H) are labeled in the photographs on the right. Reproduced with permission from Riddle et al. (Riddle et al., 1993). Photographs courtesy of C. Tabin.

View larger version (39K): [in a new window]   Fig. 2. The wing is patterned by two morphogens, Hh and Decapentaplegic (Dpp). (A) Hh produced in the posterior (P) compartment generates a short range gradient of Hh in the anterior (A) compartment. Hh both patterns the central domain of the wing and induces the expression of en, ptc and dpp, at high, middle and low thresholds, respectively, in a stripe of cells adjacent to the AP compartment boundary. Note that en is induced by Hh in the anterior compartment in late larval development. Dpp induces expression of sal and omb at high and low thresholds, respectively, and patterns the wing beyond the central domain. (B) Ectopic expression of hh results in a mirror image duplication of the entire A compartment while Dpp induces a mirror image duplication of the A compartment lacking the central domain (Zecca et al., 1995). Reproduced with permission from Tabata (Tabata, 2001).

View larger version (71K): [in a new window]   Fig. 3. Distribution of Hh, Dpp-GFP and Wg in the wing imaginal disc. Note the graded distribution away from the expressing domain.

View larger version (42K): [in a new window]   Fig. 4. Dpp signals through the Tkv receptor and directly activates target genes. (A) Signaling pathway of Dpp. Dpp is received by a complex of type I (Tkv or Sax) and type II (Put) serine/threonine kinase receptors. Binding of Dpp to this receptor complex results in the activation of the receptor complex. The activated Tkv directly phosphorylates Mad, which, upon phosphorylation, translocates into the nucleus along with Medea (Med) and regulates transcription of target genes, such as sal and omb. (B-C') Activated Tkv directly upregulates sal expression. (B) Sal in the wild-type wing disc (purple). (C,C') A clone of cells (marked by an arrowhead in C and shown in green in the merged image C') expressing an active form of Tkv (Tkv*) cause an upregulation of sal expression in a region of the imaginal disc that does not normally express sal, seen here alongside the region of imaginal disc that normally expresses sal. Note the autonomy of the upregulation of sal expression by Tkv (C').

View larger version (36K): [in a new window]   Fig. 5. Wg and its target genes. (A-D) Wg (A; shown in green) is produced along the DV border and induces the expression of target genes, such as Ac (B; yellow, and expressed only in the A compartment), Dll (C; purple) and Vg (D; red), at high, middle and low thresholds, respectively. Anterior is to the left. (E) Schematics showing the domains of target gene expression. Reproduced with permission from Briscoe et al. (Briscoe et al., 2001).

View larger version (25K): [in a new window]   Fig. 6. A model for effects of Patched (Ptc) on neural patterning. (A; left half) Shh emanating from the notochord (N) induces formation of the floor plate (FP), and subsequent shh expression in the FP generates a ventral-dorsal activity gradient of Shh (as indicated by the density of the blue dots). (B; left half) The activity gradient of Shh promotes the specification of a series of ventral cell types: p0, p1, p2, pMN and p3, which are progenitor domains from which distinct V0 neurons, V1 neurons, V2 neurons, motoneurons and V3 neurons are generated respectively. Production of a mutated form of the Shh receptor Ptc (Ptc1loop2; A; right half; light green), which does not bind Shh but antagonizes its signaling, causes cell-autonomous abnormal dorsal spread of Shh and (B; right half) ventral-todorsal switches in neural progenitor identity. Modified with permission from Briscoe et al. (Briscoe et al., 2001).

View larger version (52K): [in a new window]   Fig. 7. Ligand and activity gradient of Dpp. Confocal microscopy images (left) and schematic drawings (right) of the part of the wing imaginal disc that gives rise to the adult wing. Hh (green), the synthesis of which is maintained by Engrailed (En) in P-compartment cells, induces Dpp expression (red) along the AP border. Dpp diffuses in both A and P directions and forms a gradient, which can be visualized by the distribution of the chimeric Dpp-GFP protein (blue). The level of Tkv, the Dpp receptor (purple), is very low along the AP border because Hh downregulates its expression. In the middle of the wing disc, abutting the AP border, the level of Tkv in the P compartment is higher than it is in the A compartment, which causes a steeper Dpp gradient to be present in the P compartment than in the A compartment. This dynamic Tkv pattern accounts well for the shape of the activity gradient of Dpp signaling, as shown by the levels of phosphorylated Mad (p-Mad).

View larger version (119K): [in a new window]   Fig. 8. Hh requires HSPGs in order to move. (A,D,G) Hh distribution; (B,E,H) merged images of Hh distribution (purple), with cells of the imaginal disc marked uniformly with GFP (green). The clone of cells mutant for EXT originated from a single cell lacking EXT activity, created by mitotic recombination and marked by the absence of GFP. Thus, cells homozygous for the EXT mutant are marked by an absence of GFP and cells heterozygous for the EXT mutant are pale green. The staining intensity of Hh in the selected area (white boxes in B and E) was integrated along AP axis, plotted using NIH Image software and presented schematically (C,F). (A-C) Hh protein synthesized in the posterior compartment appears to flow into the anterior compartment, with a moderate concentration gradient starting from the middle of the posterior compartment. (D-F) Hh accumulates abnormally in the posterior compartment when the EXT mutant clone is in the anterior compartment along the AP boundary. The A/P boundary is depicted with blue lines (A,D). (G,H) When the EXT mutant clone is produced in the posterior compartment, Hh accumulation is reduced.

View larger version (54K): [in a new window]   Fig. 9. Models for morphogen transport. (A) A model for cytonemes. Cells at the periphery of the imaginal disc extend long processes, cytonemes, towards the AP border, where Dpp is expressed (light blue). (B) A model for argosomes. The basolateral membranes of imaginal disc cells vesiculate and travel throughout the disc epithelium.

View larger version (42K): [in a new window]   Fig. 10. Mirror image duplication reported by Hans Spemann and Hilde Mangold. Transplantation of dorsal rip tissue from an early gastrula of newt into another early gastrula in the region that would become ventral epidermis causes a mirror image duplication of the body axis (Spemann and Mangold, 1924). Reproduced with permission from Gilbert (Gilbert, 1997).