Cell mechanics and cell-cell recognition controls by Toll-like receptors in tissue morphogenesis and homeostasis

Abstract

Signal transduction by the Toll-like receptors (TLRs) is conserved and essential for innate immunity in metazoans. The founding member of the TLR family, Drosophila Toll-1, was initially identified for its role in dorsoventral axis formation in early embryogenesis. The Drosophila genome encodes nine TLRs that display dynamic expression patterns during development, suggesting their involvement in tissue morphogenesis and homeostasis. Recent progress on the developmental functions of TLRs beyond dorsoventral patterning has revealed not only their diverse functions in various biological processes, but also unprecedented molecular mechanisms in directly regulating cell mechanics and cell-cell recognition independent of the canonical signal transduction pathway involving transcriptional regulation of target genes. In this review, I feature and discuss the non-immune functions of TLRs in the control of epithelial tissue homeostasis, tissue morphogenesis, and cell-cell recognition between cell populations with different cell identities.

Keywords: Toll-like receptors; cell competition; cell mechanics; cell recognition; cell-cell adhesion; myosin II; planar polarity; tissue morphogenesis.

Figure 1.

Toll-like receptors in Drosophila a) Domain structures of nine Drosophila TLRs. The clade of TLRs that have common features characteristic to insect TLRs, defined as long Tolls [36], is indicated with a bracket. b) Phylogenetic relationship of Drosophila TLRs. Toll-9 is the closest Drosophila TLR to vertebrate TLR. The long Toll clade is indicated with a dashed line. c) The canonical signal transduction pathway of Toll-1. Upon binding to the active ligand Spätzle (Spz), Toll-1 is activated and its conformational change leads to the recruitment of the adapter protein MyD88 through interaction with the TIR domain, which is present both in Toll-1 and MyD88. Once MyD88 binds to Toll-1, it forms a protein complex with Tube and Pelle, which then degrades the IκB protein Cactus (Cact), subsequently inhibiting the NFκB transcription factor Dorsal (Dl) and Dorsal related immunity factor (Dif) when Toll-1 is not activated. After the degradation of Cact, Dl/Dif is released to translocate into the nucleus where it promotes transcription of its target genes.

Figure 2.

Toll-like receptors in cell competition a) The recognition of unfit cells (red cell) leads to the induction of apoptosis in epithelia (left). Once unfit cells are detected, they become loser cells and do not contribute to the tissue (right). In the case of Myc-induced cell competition, Myc-overexpressing cells become winner cells and wild type cells become loser cells. scribble (scrib) mutant clones become loser cells when surrounded by wild type cells. b) Signal transduction components of myc-induced cell competition. TLR signalling is upregulated in wild type loser cells, leading to the induction of apoptosis (top). When loser cells are defective for the transduction of TLR (e.g. loss of function of TLRs), wild type cells can survive (bottom). c) The competitive context induced by myc-induced cell competition (left). In myc-induced cell competition, the tissue is in the TLR signal activation-prone condition. Extracellular serine proteases such as Spz processing enzyme (SPE) are secreted into the lumen, and the TLR ligand Spz, which is present in the lumen, is activated, resulting in the activation of TLR signalling in wild type loser cells (top). When loser cells are defective for TLR signalling, wild type cells do not become loser cells and can survive (bottom). The competitive context induced by scrib-induced cell competition (right). The TLR ligand inhibitor Serpin 5 (Spn5) is secreted in this context. Due to the loss of TLR signalling, scrib mutant cells undergo apoptosis (top). When the cells are defective for Spn5, scrib mutants receive the active Spz and undergo the activation of TLR signalling, leading to the tumorigenic phenotype caused by over-proliferation (bottom).

Figure 3.

Toll-like receptors in the control of germband elongation a) Germband elongation of the Drosophila embryo. Embryos at stage 6 to 9 are illustrated (left). Cells that undergo convergent extension are depicted (right). Arrows indicate the direction of tissue deformation. b) Molecules and cellular mechanism of cell intercalations. Myosin II (Myo-II) is enriched on the anterior and posterior cell edges throughout the tissue, while Par-3 is enriched on the dorsal and ventral edges for each cell (left). Contraction of a vertical edge followed by the formation of the 4-way vertex and elongation of a horizontal edge after the junctional exchange results in the cell intercalation (right). c) Spatial expression patterns of TLRs. Numbers within the cells indicate TLRs expressed. Horizontal bars below the schematic indicate expression domains for referenced TLRs (left). Odd and even parasegments (PS) are indicated. Myosin-II accumulation is indicated by dashed red lines. Myo-II is still present in Toll-2,6,8 triple mutants (right). The Leucine rich repeat protein Tartan (Trn) is expressed in even parasegments. d) Two possible models of planar cell polarity. In the relay model (i), arrows depict the signal from a neighbour on one side is relayed to the neighbour on the other side. Protein activity gradients are established in each cell, resulting in the robust transmission of polarity information from one to another. The direct specification model (II) does not transmit signal from one cell row to next. The differential cell identity between neighbours is sensed directly and polarizes the cell. e) Signal transduction by Toll-2 in the regulation of planar polarity at the edge of the Toll-2 expression domain. f) Interaction of Toll-8 with the adhesion GPCR Cirl in trans and cis. trans interaction leads to a basal shift of Cirl localization, while cis interaction leads to an apical shift. The resulting asymmetry of Cirl localization leads to the recruitment of Myo-II at that cell junction.

Figure 4.

Cell-cell adhesion by Toll-like receptors in tissue morphogenesis and the wiring of the olfactory nervous system a) Differential adhesion model. Cells expressing more adhesion molecules (blue) replace the weaker adhesions with the stronger ones, resulting in the relocation of these cells inside the cell aggregate. b) Differential expression of Toll-1 in the histoblasts of the pupal abdomen. Locations of histoblast nests are indicated (top). Anterior to the left and posterior to the right. Toll-1 is strongly expressed in the posterior compartment (blue). Compartment boundary is indicated by the open arrowhead (bottom). c) Homophilic adhesion of Toll-1 between posterior compartment cells (P cells). d) Wiring between olfactory receptor neurons and projection neurons in the glomerulus. e) TLRs in the ORN-PN matching. In the VA1d glomerulus the pre-synaptic VA1d ORN and the post synaptic PN form a connection. Toll-6 functions in the PN and Toll-7 in the ORN. Toll-6 does not require the expression of Toll-7 in the cognate ORN and vice versa. Neither protein requires the intracellular domain, suggesting the presence of heterophilic binding partners.