Human tissues and organs are comprised of a multitude of individual cells. In order to build and maintain complex structures like bone and the intestine, these individual cells must communicate with each other to coordinate their actions. Cells communicate by sending out instructions in the form of signalling molecules. These signals are recognised by neighbouring cells, leading to the activation of specific signalling pathways. By regulating cell growth, death and differentiation these signalling pathways ensure organs and tissues develop to the right size, with the necessary specialized cell types needed to function correctly. Furthermore, in adult tissues and organs signalling molecules ensure tissues regenerate to replace lost or damaged cells.
As we age, these signalling pathways change, with drastic consequences for human health. In addition to the loss of tissue renewal seen in age-related diseases such as osteoporosis, altered signalling environments can also favour the uncontrolled cell growth that causes cancer. Establishing how cells signal to each other, and how these signalling systems become dysfunctional with age, will uncover how age-related diseases develop and potentially identify therapeutic interventions for their treatment.
We study two particular signalling molecules, Wnt and Hedgehog, both of which carry hydrophobic lipid modifications that complicate their ability to spread between cells and function in cell-to-cell communication. We seek to understand how these lipid modified signals are released from sending cells, how they are recognized on receiving cells and how recognition leads to activation of signalling. In addition to identifying precisely how the Wnt and Hedgehog signalling pathways operate at the cellular level, we seek to identify how they, and other signalling pathways, change in ageing organs and how such changes affect organ function. To answer these questions, we use a multidisciplinary approach involving protein and molecular biology, human cells, organoids, and Drosophila melanogaster (fruit fly) and mouse genetics.
An example of cell-to-cell communication in the developing fruit fly wing. Here a strip of cells in the middle of the organ signals to neighbouring cells by releasing a specific Wnt signalling protein called Wingless (green). Wingless spreads to and instructs neighbouring cells that receive a large amount of Wingless to switch on a specific gene called senseless (red). While those cells that receive high and medium levels of Wingless switch on a different gene called Distal-less (purple). This communication helps the developing organ to grow and attain the right cell types.
Temporal control is central to deploy and coordinate genetic programs during development. At present, there is limited understanding of the molecular mechanisms that govern the duration and speed of developmental processes. Timing mechanisms may run in parallel and/or interact with each other to integrate temporal signals throughout the organism. In this piece, we consider findings on the extrinsic control of developmental tempo and discuss the intrinsic roles of cell cycle, metabolic rates, protein turnover, and post-transcriptional mechanisms in the regulation of tempo during neural development.
Regulation of transcription is central to the emergence of new cell types during development, and it often involves activation of genes via proximal and distal regulatory regions. The activity of regulatory elements is determined by transcription factors (TFs) and epigenetic marks, but despite extensive mapping of such patterns, the extraction of regulatory principles remains challenging.
Obesity is associated with increased ovarian inflammation and the establishment of leptin resistance. We presently investigated the role of impaired leptin signalling on transcriptional regulation in granulosa cells (GCs) collected from genetically obese mice. Furthermore, we characterised the association between ovarian leptin signalling, the activation of the NOD-like receptor protein 3 (NLRP3) inflammasome and macrophage infiltration in obese mice. After phenotype characterisation, ovaries were collected from distinct group of animals for protein and mRNA expression analysis: (i) mice subjected to a diet-induced obesity (DIO) protocol, where one group was fed a high-fat diet (HFD) and another a standard chow diet (CD) for durations of 4 or 16聽weeks; (ii) mice genetically deficient in the long isoform of the leptin receptor (ObRb; db/db); (iii) mice genetically deficient in leptin (ob/ob); and (iv) mice rendered pharmacologically hyperleptinemic (LEPT). Next, GCs from antral follicles isolated from db/db and ob/ob mice were subjected to transcriptome analysis. Transcriptional analysis revealed opposing profiles in genes associated with steroidogenesis and prostaglandin action between the genetic models, despite the similarities in body weight. Furthermore, we observed no changes in the mRNA and protein levels of NLRP3 inflammasome components in the ovaries of db/db mice or in markers of M1 and M2 macrophage infiltration. This contrasted with the downregulation of NLRP3 inflammasome components and M1 markers in ob/ob and 16-wk HFD-fed mice. We concluded that leptin signalling regulates NLRP3 inflammasome activation and the expression of M1 markers in the ovaries of obese mice in an ObRb-dependent and ObRb-independent manner. Furthermore, we found no changes in the expression of leptin signalling and NLRP3 inflammasome genes in GCs from db/db and ob/ob mice, which was associated with no effects on macrophage infiltration genes, despite the dysregulation of genes associated with steroidogenesis in homozygous obese db/db. Our results suggest that: (i) the crosstalk between leptin signalling, NLRP3 inflammasome and macrophage infiltration takes place in ovarian components other than the GC compartment; and (ii) transcriptional changes in GCs from homozygous obese ob/ob mice suggest structural rearrangement and organisation, whereas in db/db mice the impairment in steroidogenesis and secretory activity.