The interplay between morphogens and tissue growth

Abstract

Morphogens are conserved, secreted signalling molecules that regulate the size, shape and patterning of animal tissues and organs. Recent experimental evidence has emphasized the fundamental role of tissue growth in expanding the expression domains of morphogens and their target genes, in generating morphogen gradients and in modulating the response of cells to morphogens. Moreover, the classic view of how morphogens, particularly through their concentration gradient, regulate tissue size during development has been revisited recently. In this review, we discuss how morphogens and tissue growth affect each other, and we attempt to integrate genetic and molecular evidence from vertebrate and invertebrate model systems to put forward the idea that the interaction between growth and morphogens is a general feature of highly proliferative tissues.

Figure 1

Growth contributes to expanding the expression domains of morphogens and their target genes. (A) Distinct molecular mechanisms contribute to the expansion and robust expression of morphogens and their target genes in highly proliferative Drosophila tissues. Transcription factors (TFs) that are active in restricted domains bind to cis-regulatory elements (enhancers) and activate or repress gene expression (note that the vestigial enhancer is located in an intron). The Polycomb responsive element (PRE) and maintenance element (ME) act as memory modules and contribute, together with tissue growth, to the expansion of the expression domain of these genes. (B) The ‘trigger-maintenance’ mechanism contributes to the expression of hedgehog (in red) and vestigial (in green) in the Drosophila wing, as well as Distalless (grey) in the Drosophila leg. hh and vestigial are initially expressed in a restricted pattern (dark red and dark green, respectively). As the tissue grows, new cells (light red and light green, respectively) inherit the expression of these genes by an epigenetic mechanism that depends on the activity of PcG and TrxG. In the case of Distalless, a leg trigger element integrates Wg and Dpp inputs (dark grey). As cells proliferate, Distalless binds to a maintenance element in an autoregulatory loop that sustains morphogen-independent expression in newly generated cells (light grey). Su(H), TCF and Mad are the nuclear effectors of the Notch, Wg and Dpp signalling pathways, respectively. d, dorsal; Dpp, Decapentaplegic; hh, hedgehog; PcG, Polycomb group proteins; Su(H), Suppressor of Hairless; TrxG, Trithorax group proteins; v, ventral; Wg, Wingless.

Figure 2

Growth modulates the response to morphogens. (A) The developmental decision between wing and body wall is defined by the antagonistic activities of Wg and Vein, expressed at opposite sides of the wing primordium. Early in development, high levels of Vein block Wg-induced wing-fate specification. An increase in the size of the tissue pulls the sources of Wg and Vein apart, facilitating the response of the cell to the wing-inducing activity of Wg. Wg- and Vein-expressing cells are shown in dark purple or dark green, respectively, and the range of diffusion is depicted in light purple or light green. (B) Two signalling centres are found in the vertebrate limb primordium: FGFs are synthesized in the AER (in red), and Shh is produced in the ZPA. Through a positive feedback, Shh and FGFs maintain each others' expression, and the loop is crucial for producing a normal limb structure. Growth of the vertebrate limb-bud along the anterior–posterior axis and specification of the digits is regulated by Shh. Tissue growth helps to generate the Shh gradient and expands the Shh non-expressing domain. Cells far from the source, and thus receiving low levels of Shh, generate anterior digits. Cells exposed to higher levels of Shh and for a longer period generate posterior digits. Specification of cell-fate identities along the proximal–distal axis, in turn, is controlled by the antagonistic activities of retinoic acid and FGFs, which are expressed at opposite sides of the limb bud. Growth along the proximal–distal axis modulates the response of cells to FGFs and retinoic acid, and helps in generation of the proximal (stylopod), medial (zeugopod) and distal (autopod) segments of the adult limb. AER, apical ectodermal ridge; FGF, fibroblast growth factor; RA, retinoic acid; Shh, Sonic hedgehog; Wg, Wingless; ZPA, zone of polarizing activity.

Figure 3

Morphogens and tissue growth. (A) The Dpp (blue), Hh (grey) and Wg (red) morphogens are expressed in restricted domains. Dpp expression relies on the activity of Hh, which is expressed in posterior cells and acts as a short-range morphogen. Wg and Dpp act as long-range morphogens. (B) Dpp and Wg have a permissive role in promoting tissue growth in the Drosophila wing by inhibiting the expression or activity of proteins that repress growth. Dpp inhibits expression of the transcriptional repressor Brinker, which represses growth by an unknown mechanism, whereas Wg represses Notch activity, which is known to inhibit the expression of the proto-oncogene dMyc and the growth-promoting microRNA bantam. A, anterior; D, dorsal; Dpp, Decapentaplegic; P, posterior; V, ventral; Wg, Wingless.

Figure 4

Morphogen-induced subdomains contribute to regulation of final tissue size. (A) The subdivision of a growing tissue into secondary domains has a crucial role in tissue growth. Hh (grey) induces expression of Dpp (blue) in anterior cells. Spalt (orange) is a target of Dpp in the wing. The boundary between spalt-expressing and non-expressing cells defines the location of the longitudinal vein L2. Loss of spalt in the whole anterior compartment (grey) gives rise to smaller adult wings. Note that the anterior compartment consists of three intervein regions in wild-type wings, but only two in the absence of spalt activity. The boundary between the anterior (A) and posterior (P) compartments is shown by a dashed line. (B) Depletion of Shh activity at different times of limb primordium development reduces the size of the adult limb and causes loss of adult digits. Dpp, Decapentaplegic; Hh, Hedgehog; Shh, Sonic hedgehog.

Andrés Dekanty

Marco Milán