We study RNA modifications and their role in germ cell proliferation and differentiation.

During development cells constantly face a decision between cell division and differentiation. Regulation of gene expression is key to this decision making process. RNA is at the centre of many gene regulatory processes.

There are more than 150 distinct chemical modifications found on RNA. RNA modifications control the processing, stability, expression and function of diverse types of RNAs.

For the majority of RNA modifications, we don’t know their biological role in multicellular organisms. We use the nematode Caenorhabditis elegans. The germline development of C. elegans provides an ideal model system to study the role of RNA modifications and RNA modifying enzymes in cell proliferation and differentiation.

We investigate the early stages of eye development to understand how genes give rise to the geometry of living matter, and to shed light on inherited malformations of complex organ systems. Our research explores the genetic networks that organise tissues (patterning) and cell dynamics that translate pattern into form (morphogenesis).

We work to genetically dissect the role/s of Fibroblast Growth Factor (FGF)/ FGF receptor (FGFR) signaling system in mammalian organogenesis and adult stem cell function. In the past, we have elucidated these roles in the developing craniofacial sutures, axial skeleton, limbs, lungs, genitalia, submandibular glands and the developing nervous system. Our model organism and research tool is transgenic mice that allow lineage tracing in conjunction with loss and gain-of function in FGFs, FGFRs or FGF signaling mediator genes. In particular, we have generated and studied gain-of-FGFR1 and FGFR2 mutant mice that model two congenital craniosynostosis diseases: Pfeiffer and Apert syndromes. Currently we are interested in novel populations of slow-dividing/ quiescent stem/progenitor cells in the postnatal/adult brain, with a view to understanding their normal role in brain function and exploiting their potential to alter physiology and brain repair. In particular, a novel neurogenic niche in the postnatal and adult hypothalamus, wherein tanycytes that express FGF10 act as neural stem cells and supply the hypothalamic neural circuits with new neurons. Our in vivo studies are complimented by in vitro and ex vivo model systems to delineate the molecular role of FGF signaling in stem/ progenitor cell growth and differentiation. 

In our lab, we are interested in genetics and reproduction and use a wide range of approaches including experimental studies, mathematical modeling, genetics and genomics. We work on a multitude of organisms with a main focus on zebrafish and humans. Zebrafish because they are perfect for experimental work and in vitro fertilisations and we can use fantastic tools such as gene knockdown and knockout to study functional genetics and genomics. Humans because we still know so surprisingly little about human reproduction.

Our group aims at understanding the role cell-extracellular matrix interaction plays in development and tissue maintenance in the adult. Using mice as a model system, we are interested to unravel the mechanisms by which cells direct extracellular matrix composition, and vice versa, how the environment influences cellular behaviour. In recent years, we have focused our research on the function of cell surface receptors for skeletal muscle maintenance and regeneration and the role of muscle stem cells as potential therapeutic target in muscle wasting diseases, such as Duchenne muscular dystrophy. 

My primary research interest focusses on how the early vascular system, made up of blood and blood vessels, arise during embryonic development - specifically a group of cells called hemangioblasts - using the chick embryo as a model organism. I use a combination of experimental and computational approaches to study how transcription factor networks (also known as gene regulatory networks) control the function of the vascular system made up of hematopoietic (blood) and endothelial (blood vessels) cells. We use an integrated approach of genomics (single cell sequencing) and molecular and cellular biology (live imaging) to discover new combinatorial interactions between key hemato-endothelial cell regulators. This work is currently funded by the British Heart Foundation (BHF).

Epigenetics is the term used in biology to refer to chromatin structure and DNA modifications that are stable over rounds of cell division but do not involve changes in the DNA sequence. Epigenetics play a pivotal role in cellular differentiation, allowing cells to stably maintain different characteristics despite containing the same genomic DNA. Epigenetic processes are also involved in gene silencing, X chromosome inactivation, reprogramming and are thought to be one of the major limitations to cloning. One of the main interests of this group is Genomic Imprinting. Imprinted genes are expressed from only one parental allele, the other is silenced by epigenetic modifications, classically involving DNA methylation and asymmetric chromatin structure. Imprinted genes are typically involved in embryonic growth and development. Abnormal imprinted gene expression is one of the most frequent aberrations in carcinogenesis.

The group investigates embryonic development and how it is controlled at the molecular level. We use the chick as a model to study vertebrate development, because the embryo is easy to access in the egg. In particular, we look at the signals that control cell migration and cell fate decisions. For example, future heart cells are ‘born’ at an early embryonic stage and then migrate long distances to where the heart forms. The same is true for the cells that will become the skeletal muscles in our body which are derived from structures called somites. During their migration the cells are also instructed to adopt specific fates and the two processes, migration and fate specification, go hand-in-hand. Our work aims to decipher the molecular and cellular mechanisms driving this. The insights we gain increase our understanding of early embryo development, but the research is also important for stem cell science and regenerative medicine, because similar mechanisms to those acting in embryos govern stem cell differentiation and tissue repair. We use the mouse as a model for studying tissue repair, in particular how muscle is able to regenerate.

My research focus is in understanding the cellular and genetic mechanisms that underlie cell-fate decisions during:

• Embryogenesis, maintenance and repair/regeneration of the cardiovascular and pulmonary systems, and

• Direct nuclear programming of somatic cells to pluripotency and cardiovascular/pulmonary fates.

The knowledge gained from this understanding is being used to bring cellular and gene therapies to the translational phase for drug development, tissue regeneration and replacement and gene corrections/enhancements in vivo. We are also working to better understand the different states of pluripotency in mammals.

The Smith Lab uses pluripotent stem cells and gene editing techniques to model the molecular mechanisms behind human diseases. Human induced pluripotent stem cells (hiPSCs) can be differentiated into any cell type of the body. By editing the genes of these cells and then differentiating these into specific cell types, we gain understanding of the roles these genes and mutations play within disease.  Specific interests include cardiovascular diseases such as hypertrophic cardiomyopathy, cardiac fibrosis and left ventricular non compaction.

My group works on the molecular events that govern the origin and migration of different cell types within the developing Xenopus embryo. To investigate these processes we are using a combination of developmental biology, imaging and chemical genetic approaches. We are also interested in developing Xenopus as a potential tool for use in the drug screening and discovery process. We are mainly focussed on looking at the specification, differentiation and migration of Neural Crest cells especially with respect to pigment cell development and melanoma growth.