Edinburgh Research Explorer

Prof Bob Hill, PhD

Programme Leader

Willingness to take Ph.D. students: Yes

Biography

I received my PhD from the University of Tennessee in 1981 and spent one and a half years at the Roswell Park Memorial Institute in New York.  I have been with the MRC in Edinburgh since 1983 first as a postdoctoral fellow and then as a principle investigator.  My major area of study is developmental genetics using the mouse as our experimental model.  Our interests have been in transcription factors and their roles in mammalian development and have primarily focused on processes that occur during organogenesis.  We isolated some of the first developmental genes in the mouse and focused initially on the homeobox containing genes.  We showed a correlation between the mechanism by which these genes operate in segmenting regions of the mouse hindbrain and in Drosophila segmentation.   We went on to show the position dependence of cells expressing homeobox containing genes and that tissue could be reprogrammed by changing position in the embryo.  We were among the first to show that the homeobox containing class of genes, in particular Pax6, was involved in human disease.  Pax6 is the basis for a congenital form of blindness called aniridia.  Our work opened up a molecular understanding of eye development with our initial studies on the roles of Pax6.  In our studies on gut development we have defined a new organising centre (we called the splanchnic mesodermal plate[SMP]) that is responsible for the left/right asymmetrical development of the spleen pancreas and stomach.   Most recently we have defined the molecular basis for preaxial polydactyly (PPD) in human. This has led to the establishment of a new genetic mechanism for congenital diseases.  The mutations for cause PPD all lie within a regulatory element controlling expression of the signalling molecule, Sonic Hedgehog.  These point mutations, rather than inactivate expression, redirect expression to an ectopic site.  I have been awarded my Professorship at the University of Edinburgh Medical School.

Qualifications

BSc, PhD

Current Research Interests

Throughout my career I have focused on mechanisms responsible for organogenesis during embryonic development.  Initially the mechanisms that provoke a differentiated cellular phenotype were explored by isolating a family of liver-specific genes encoding serine protease inhibitors.  Analysis of this family led to several papers on the evolution of this gene family.  This work led to two Nature papers, one (1987) a landmark paper showing accelerated gene evolution with molecular evidence for Darwinian evolution, concepts supported by a number of studies since publication of this paper.  Soon afterwards deep conservation of developmental genes became apparent and Hill set out to isolate and analyse homeobox genes in mouse.  My group reported the isolation and expression of some of the first mammalian Hox genes [Nature 1989], demonstrating the expression of the Hoxa & Hoxb cluster genes in the previously controversial rhombomere structures of the hindbrain.  These studies related hindbrain segmentation to similar concepts in the segmentation process of the Drosophila embryo and laid the foundation for establishing the Hox code in mice.  Subsequently, the group showed (collaboratively) that mutations in another homeobox containing gene, Pax6, were responsible for the mouse small eye phenotype which led to the finding that Pax6 is responsible for the human disorder aniridia.  Pax6 and Pax3, were the first examples of developmental gene involvement in human disease, now a commonplace concept. Since these initial reports Hill’s group published a number of detailed papers on eye and brain development. Recent Pax6 studies have focused on the stem cell population that give rise to the cornea.  They have also reported on a number of other developmental homeobox genes which they had identified, including members of the Engrailed and Msx gene family and the Bapx1 gene. 

Latterly, my group’s interests have revolved around pattern formation during limb development focusing on skeletal abnormalities and left/right asymmetry focusing on visceral heterotaxias. Initially, studies on limb development (Nature, 1991) showed positional control of homeobox gene expression in the limb.  We followed these studies with the analysis of a common limb disorder, pre-axial polydactyly (extra digits). We established a paradigm: a novel disease mechanism in which point mutations in a cis-regulatory element a million bases from the Shh gene causes ectopic expression of the signalling molecule.  Recently, the protein factors responsible for regulation at this site have been identified and shown to be involved in the disease process (unpublished).

Key interests in left/right asymmetry led the group to explore the programmed positioning of the viscera.  Abnormalities of this process result in cardiac disorders, asplenia, polysplenia, stomach and gut malrotations.  We defined how information is conveyed from the early mesoderm to the gut endoderm, so regulating asymmetric organ growth. We identified the cellular and developmental mechanisms directing spleen, pancreas and stomach growth to the left side of the body cavity establishing the previously unknown events leading to spleen development.

Lastly, my group collaborates with clinicians to develop animal models for human developmental anomalies.  These are increasingly important skills for validating whole genome sequence data and progressive molecular diagnosis.

 

Research Interests

We are investigating the chromatin dynamics and the epigenetic changes that occur during the expression of a gene that controls mammalian development and the affect of mutations that cause congenital abnormalities.

Research Groups

Mark Ditzell (IGMM)

David Fitzpatrick (IGMM)

Andrew Jackson (IGMM)

Julia Dorin (IGMM)

John West (Reproductive & Developmental Sciences)

Stuart Ralston (IGMM)

Donald Salter (IGMM)

My research in a nutshell

During embryonic development complex processes operate to form our organ and skeletal systems. Genetic changes that disrupt any of these processes can lead to birth defects.  Our aims are to uncover these genetic mutations and establish how these changes disrupt the normal processes of development. We are investigating the basis of two very different developmental abnormalities; the first is called preaxial polydactyly (PPD), a related group of abnormalities that affect development of the skeleton of the arms and legs and the second is Matthew-Wood Syndrome (MWS) a lethal condition in newborns that affects the heart, lungs eyes and other organ systems. 

We previously established the genetic basis of both of these birth defects and now are working to gain a molecular and biochemical understanding.  One direction for our studies has been the production of mouse models for these birth defects which provide a means to exam the disease mechanisms and indeed to delve into normal developmental processes.  These models show that both defects disrupt potent cellular communication pathways in the embryo.  PPD causes the pathway to be produced in the wrong place in the developing limbs and we are attempting to understand the mechanisms that can cause such a mis-localisation of this important developmental pathway.  A chain of biochemical events are required to initiate the pathway affected by MWS.  MWS mutations disrupt this chain at an early step and we are attempting to fully understand the range of developmental events disrupted as a consequence.  The pathway involved is also a good example of a developmentally important process continuing to play a role well after birth.  We are investigating the suspected role of this pathway in inflammation, obesity and diabetes. 

Highlighted research outputs

  1. Ribonuclease H2 mutations induce a cGASSTING-dependent innate immune response

    Research output: Contribution to journalArticle

  2. Variation in vertebrate cis-regulatory elements in evolution and disease

    Research output: Contribution to journalLiterature review

  3. Mapping the Shh long-range regulatory domain

    Research output: Contribution to journalArticle

  4. Long range regulation of the sonic hedgehog gene

    Research output: Contribution to journalArticle

  5. Enhancers: from developmental genetics to the genetics of common human disease

    Research output: Contribution to journalArticle

  6. Human limb abnormalities caused by disruption of hedgehog signaling

    Research output: Contribution to journalArticle

  7. Anterior-posterior differences in HoxD chromatin topology in limb development

    Research output: Contribution to journalArticle

  8. Enhancer-adoption as a mechanism of human developmental disease

    Research output: Contribution to journalArticle

View all (63) »

Research projects

  1. ALBERT SANCHEZ-RIBALTA ROTATIONAL DTA'S

    Project: Funded ProjectResearch

  2. IGMM CORE AWARD YR13/14

    Project: Funded ProjectResearch

  3. ROTATIONAL STUDENTSHIP - LORA BOTEVA

    Project: Funded ProjectResearch

View all (44) »

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