Immune cells images with help from the Crick's Light Microscopy STP.

Introduction

My group is interested in signal transduction pathways in B and T cells that control their survival, differentiation, adhesion and migration. We are also investigating the genetic and cellular pathological mechanisms that cause Down Syndrome phenotypes.
 

Immune Cell Biology

Signals from cell surface receptors play critical roles in B and T cell development, activation, migration, survival and death.We are studying how signalling pathways control these processes, using mouse genetics, protein biochemistry, imaging, cell biology, and RNAi and CRISPR screens. Current research interests include pathways controlling B and T cell migration and adhesion, B cell survival, the biology of memory B cells and the function of long non-coding RNAs in lymphocyte biology.

We are studying how signalling pathways control B and T cell development.

Figure 1: BAFFR transduces survival signals via the BCR. BAFFR transduces survival signals, via Src-family kinases (SFK) leading to the phosphorylation of the ITAM motif on BCR-associated CD79A and subsequent recruitment and activation of the SYK tyrosine kinase. SYK in turn transduces signals leading to activation of ERK MAPkinase and PI3 kinase pathways. BAFFR also transduces signals via NIK and IKK1 to the non-canonical NF-kB pathway. Other possible pathways supporting B cell survival are illustrated above. For more details see Schweighoffer et al Curr Opin Cell Biol (2018).


Genetics of Down syndrome

Trisomy of human chromosome 21 (Hsa21) occurs in around one in 750 live births, and the resulting gene dosage imbalance gives rise to Down syndrome (DS), the most commonly known genetic form of cognitive impairment. In collaboration with Professor Elizabeth Fisher (Institute of Neurology, UCL) we are interested in identifying dosage-sensitive genes on Hsa21 which, when present in three copies, cause the many different phenotypes seen in DS. To address this, we have created a large number of mouse models with duplications of different regions of the mouse genome orthologous to Hsa21. Using these novel strains, we are identifying the causative genes causing cognitive impairment, congenital heart defects, craniofacial abnormalities and neurodegeneration, and studying the underlying pathological mechanisms.

Mouse mapping panel

Mouse mapping panel for Down Syndrome.

Figure 2: Mouse mapping panel for Down Syndrome.

Human chromosome 21 (Hsa21) is shown on the left in a diagram illustrating the centromere (oval) and the long and short arms of the chromosome.

The long arm of Hsa21 is orthologous to regions of 3 different mouse chromosomes, Mmu16, Mmu17 and Mmu10 (grey bars). We have constructed a series of mouse strains (Dp1Tyb – Dp9Tyb) with duplications of different sections of the Hsa21-orthologous region on Mmu16 (black bars). Dp1Tyb is duplicated for a 23 Mb region from Lipi to Zbtb21, containing 148 coding genes and covering the entire orthologous region on Mmu16. This panel of mouse strains can be used to map the location of dosage-sensitive genes that are required in three copies to cause DS phenotypes (Lana-Elola et al 2016).

Selected publications