Fish and mouse

During vertebrate development the rostral most part of the neural plate differentiates into the forebrain,

the most complex region of the central nervous system (1). Previously, it was shown that depletion of

canonical Wnt signalling is required for the induction of anterior neural fates including telencephalon,

hypothalamus and eye-field. Inside this anterior forebrain territory, the mechanism by which the

telencephalon and eye field fates are established is unknown. The eye-field develops medio-laterally,

whereas the telencephalon is located at the rostral margin surrounding the eye-field laterally and

anteriorly. A graded radial signal, distinct from Wnt antagonists, secreted along the neural plate border is

well suited to induce a horseshoe-shaped telencephalon at the margin, with the eye-field at a more

medial position.

One such signal is Bone Morphogenetic Protein (BMP), which is expressed in the non-neural ectoderm

surrounding the neural plate both laterally and anteriorly throughout gastrulation (2–4). Work in both of

our labs has recently shown that the BMP pathway is active in the anterior neural ectoderm during late

blastula to early gastrula stages in zebrafish, and the Houart lab has shown it is required for establishment

of the telencephalon fate and morphogenetic movements during neurulation (5). Bmp2b mutants and

mosaic loss-of-function experiments reveal that BMP acts as a repressor of eye-field fate through

inhibition of its key transcription factor Rx3, thereby protecting the future telencephalon from acquiring

eye identity. This BMP-driven mechanism initiates the establishment of the telencephalon, prior to the

involvement of Wnt antagonists from the anterior neural border.

The proposed project has grown out of a joint interest in our two labs in the control and function of

BMP signalling in early vertebrate development. It aims to understand how the BMP activity in the anterior

ectoderm defines telencephalic fate.

The main questions we aim to answer are:

- Is BMP activity is required at a specific intensity to define telencephalic fate and movement, or is

it rather a specific duration of time of activation in the life of the precursors that defines their

fate?

- Is the requirement for BMP activity conserved in mammals, such as mice?

- What are the direct Smad target genes downstream of the signalling activity in the telencephalic

precursors?

- What is the functional molecular network, downstream of BMP, that leads to repression of eye

fate and control of cell motility inside the anterior neural plate?

The project will be carried out as a collaboration between the Houart lab, who are experts in

neurobiology in fish and mice, and the Hill lab, who are experts in BMP signalling. The findings obtained

will impact on both neurodevelopment and cell biology. Moreover, since BMP activity is deregulated in

cancer, this work has the potential to bring new insights in the mechanisms of tumourigenesis and

metastasis.

This proposal is an approximate plan of the sort of collaborative project available with these two

research groups. The precise project will be decided on in consultation with both supervisors.

1. Cavodeassi F, Houart C. (2012) Brain regionalization: of signaling centers and boundaries. Dev

Neurobiol. 72: 218-33

2. Ramel MC, Hill CS. (2013) The ventral to dorsal BMP activity gradient in the early zebrafish embryo

is determined by graded expression of BMP ligands. Dev Biol. 378: 170-82.

3. Reichert, S., Randall, R.A. and Hill, C.S. (2013) A BMP regulatory network controls ectodermal cell

1) fate decisions at the neural plate border. Development. 140: 4435-4444.

Queen Mary

1) Biophysics and Mechanics of Stem Cells

Supervisor: Dr. Núria Gavara Tel: [phone], E-mail: [e-mail]

Project Details:

The project aims at characterizing the effect of mechanical stimuli on the differentiation of adult human mesenchymal stem cells (hMSCs). In particular, the project will assess the role of the cytoskeleton as bridging structure between the mechanical input and the cell nucleus. Experiments will combine state-of-the-art fluorescence microscopy techniques with Atomic Force Microscopy, cell stretch or microfluidic devices.

The candidate will routinely:

• Use cell culture, basic biochemical techniques and live-cell imaging.
• Perform biophysical experiments with diverse instrumentation such as Atomic Force Microscopes, commercial systems to apply mechanical load and microfluidic devices.
• Implement image and signal processing algorithms for data analysis.

Applicants should have a MEng/MSc/MRes in Biophysics, Cell Biology, Biomedical Engineering, Physics or similar. Experience in some of these key areas is required: cellular biophysics, fluorescence microscopy, image processing, atomic force microscopy, cell culture, basic biochemistry and Matlab.

2) Role of pituitary stem cells in development and tumorigenesis

Academic supervisors: Dr C Gaston-Massuet and Professor M Korbonits

Applications are invited from graduates with a BSc (First or Upper Second) or MSc (Distinction or Merit). Previous research experience would be an advantage. This 3 year studentship will commence on 1st October 2015 and the applicant will be based in the School's Charterhouse Square Campus. This is an exciting opportunity for a graduate from disciplines related to developmental genetics, molecular cell biology and cancer.

Background: The hypothalamic-pituitary (HP)-axis is a master regulator of many vital physiological functions. It is essential for life as it secretes hormones that control, among other functions, growth, reproduction, lactation, metabolism and the stress response. Abnormal development of the HP axis during embryogenesis results in severe endocrine dysfunction with multiple clinical phenotypes. Stem cells are critical for organogenesis of the HP-axis and abnormalities arising in the stem cell pool results in a lack of terminally differentiated endocrine cells1. Throughout life, pituitary stem cells (PSC) control the homeostasis of this organ by mobilizing cells to become specific hormone-producing cells upon physiological demands. We have identified that this process occurs under genetic regulation of Wnt/β-catenin pathway and when this pathway is over-active in the PSC, for example due to somatic activating mutations in β-catenin, it leads to over-proliferation of precursor pools and pituitary tumours called craniopharyngioma (CP). These tumours are aggressive in nature as they invade vital nearby structures such as the hypothalamus and the optic nerves, have high rates of recurrence and lead to severe morbidity and even mortality. However, the precise genetic control of PSC is not understood and how PSC contribute to pathogenic conditions such as pitutiary adenomas remains elusive.

The overarching aim of this project is to understand how PSC are genetically regulated and which is the transcriptional program that controls its physiology and homeostasis during development and disease. Specifically using state-of-the art novel transgenics murine models and isolation of stem cell in vitro the student will

Aim 1) Perform comparative transcriptome analysis of PSC in transgenic mutant lines important in pituitary development and oncogenesis: We have identified genetic pathways critical for PSC regulation such as Eph:EphrinBs. The student will use our already established transgenic colonies that allow cell lineage tracing by activation of green fluorescent protein in PSC allowing its isolation using fluorescent activated cell sorting (FACS). We will perform comparative gene-expression analyses using high-throughput sequencing technologies (RNA-seq) and identify the transciptinal program of these cells under both normal pituitary develoment and pituitary tumours.
Aim 2) We will use in-silico methods & laboratory based analysis (Chip-assay) to validate direct transcriptional programs that affect the homeostatic control of PSC.

Outcomes: The identification of PSC-molecular signature will allow us to i) identify compounds to mobilise/activate PSC and ii) identify targeted therapies for cancer stem cells that could be used in pituitary disease such as pituitary adenomas.

Techniques involved in the project: The PhD student will become proficient in a broad range of techniques: basic embryology, transgenics manipulation, microarray analysis and molecular and stem cell biology techniques. In addition to standard molecular biology techniques (such as: nucleic acid extraction, RT-PCR, western blotting, immunohistochemistry, sequencing and plasmid preparation), the student will acquire excellent state-of-the-art training in transgenic modelling of human tumorigenesis and stem cell biology using already established transgenic colonies within the host laboratory. The student will learn experimental design, interpretation of data and presentation skills in this exciting project at the boundary of stem cell biology, developmental genetics and cancer.

Informal Enquiries can be made to: Dr C Gaston-Massuet e-mail: [e-mail]

Imperial College London

1) Neural stem cell regulation by the vascular niche

· In the adult brain neurogenesis continues in two specialised regions, the subgranular zone and the subventricular zone, where neural stem cells continuously produce new neurons and glia throughout life. Stem cell function is tightly controlled by a complex interplay between cell-intrinsic programs and cell-extrinsic cues provided by the microenvironment, or niche, in which the stem cells reside. Understanding the mechanisms that underlie neural stem cell biology has the potential to identify new strategies to harness neurogenesis for the treatment of brain injuries and neurodegenerative disorders.

Our group aims to dissect the cellular and molecular mechanisms by which the niche regulates neural stem cell behaviour and fate decisions. Building on previous findings from our laboratory, the project will continue to explore how cell-cell interactions with the niche vasculature coordinate neural stem cell quiescence, self-renewal and differentiation, with an emphasis on cell-cell contact-dependent signalling. The student will use the subventricular zone as a model system and combine primary cultures, co-cultures and mouse models for this project. The successful candidate will have the opportunity to learn and utilise a variety of biochemical, optical imaging, high-throughput sequencing, cell and molecular biology techniques, while benefitting from the state-of-the-art facilities of the CSC and its vibrant research environment.

·

· Funding Notes:

· The MRC Clinical Sciences Centre has eight UK/EU studentships available for our 3.5 year PhD programme commencing October 2015. We also have a limited number of fully-funded PhD studentships available for international applicants: the application procedure is the same for both types of applicant. These studentships provide a generous stipend (currently £19,000), tuition fees and bench fees for 3.5 years.

For more information and an application form please follow the Apply Online link on this page.

CVs will not be accepted; you must fill out the application form available on the CSC website

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