Differentiation of the hypothalamus

Lead Research Organisation: University of Sheffield
Department Name: Biomedical Science

Abstract

Your body is made up of millions of different cells, which work together in a co-ordinated way. One group of cells that are really important in co-ordinating your body are nerve cells. A single nerve cells can integrate all sorts of information, decide what to do with it, and then instruct another cell to carry out a task in response.
It is difficult to exaggerate just how important are a set of nerve cells that are found in a small region of your brain, called the hypothalamus. Nerve cells here are responsible for maintaining your constancy: your temperature, weight, mood, to name but a few. They act by controlling other cells in a tiny gland just next to them ? the pituitary gland. Cells in the pituitary gland release hormones in response to messages sent to them from hypothalamic nerves.
Despite the huge importance of the hypothalamus, we know very little about how it forms in the embryo. Why do we want to know this? It is because the nerve cells that are found in the adult hypothalamus are actually born in the embryo. If we can understand how they develop normally, then we can hope to understand how they go wrong in disease and disorders. We may even be able to use stem cell technology to create new hypothalamic nerves.
Many of the questions that we wish to address in this proposal deal with the basic development of the hypothalamus: how do specific cell types arise within the hypothalamus?; how do early embryonic cell types underpin the later cells in the hypothalamus?; are the different regions of the later hypothalamus already set aside in the early embryo?

Technical Summary

The proper functioning of the nervous system depends on the highly intricate patterning, regionalisation and specification of neural progenitor cells that occurs during embryogenesis. Recently we have shown that the ventral-most cells of the hypothalamus share an origin with floor plate cells. Like floor plate cells, ventral-most hypothalamic cells possess organiser activity, patterning and specifying cells in both the dorsally-adjacent neurogenic hypothalamus. The co-ordinated architecture of hypothalamic neurons is likely to be an instrumental component in the integrated development and function of the hypothalamo-pituitary-adrenal neuroendocrine axis, an axis that controls body homeostasis. These studies aim to examine the development and functional properties of ventral hypothalamic cells,and examine the specification and differentiation of cells in the neurogenic hypothalamus.

Many of the experiments within these categories follow the same general outline. In the first instance, we will analyse the chick embryo, perform in vivo and in vitro experiments/analyses, and test hypotheses through both gain-of-function and loss-of-function studies. Our background studies suggest that conditonal experiments will be critical to unravel hypothalamic development. The chick provides a particularly powerful model organism to study hypothalamic development, due to the ease with which it can be manipulated in both a spatial and temporal conditional manner. We will manipulate transcription factor codes in the hypothalamus through targeted electroporations. We will manipulate signals and signalling pathways in both in vivo and in vitro assays. We have extensive expertise in these areas. We will couple all these studies with fate-mapping analyses, since our previous studies have shown that cel migration events play a key role in hypothalamic ontogeny. However, in the longer-term, we will, where possible, use mouse mutants to assess whether hypotheses that derive through chick experiments are more broadly applicable.

My lab is well-equipped to perform these experiments and we have extensive experience in this area of research. There is a very real need to understand the ontogeny of the hypothalamus, since disorders of the hypothalamo-pituitary axis leading to aberrant homeostasis are likely to affect huge numbers of individuals.

Publications

10 25 50
 
Description Roslin scientific advisory board panel member
Geographic Reach National 
Policy Influence Type Participation in advisory committee
 
Description Use of animals in Medical Research
Geographic Reach Europe 
Policy Influence Type Membership of a guidance committee
 
Title Assay for establishment of pituitary stalk, description of novel role for FGFs 
Description Growth factor: role in axonal guidance 
Type Of Material Model of mechanisms or symptoms - in vitro 
Provided To Others? No  
Impact NA 
 
Title Hypothalamic stem cell niche description 
Description Mouse resource 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2008 
Provided To Others? Yes  
Impact Collaborations established 
 
Title Model of hypothalamic development 
Description In vitro explant culture and associated cell line as tool for hypothalamic cell development 
Type Of Material Model of mechanisms or symptoms - in vitro 
Year Produced 2007 
Provided To Others? Yes  
Impact Working up cell line for knowledge transfer purposes 
 
Description Analysis of adult hypothalamic stem cells 
Organisation Harvard University
Department Harvard Medical School
Country United States 
Sector Academic/University 
PI Contribution In vitro evidence for adult neural stem cells in hypothalamus, and role of FGFs in heir regulation
Collaborator Contribution In vivo analysis of adult mouse neural stem cellsTechniques for analysis of adult neural stem cells
Impact Manuscript in review
Start Year 2007
 
Description Analysis of adult hypothalamic stem cells 
Organisation Harvard University
Department Harvard Medical School
Country United States 
Sector Academic/University 
PI Contribution In vitro evidence for adult neural stem cells in hypothalamus, and role of FGFs in heir regulation
Collaborator Contribution In vivo analysis of adult mouse neural stem cellsTechniques for analysis of adult neural stem cells
Impact Manuscript in review
Start Year 2007
 
Description Role of FGFs in establishing the hypothalamo-neuroendocrine axis 
Organisation University of Cologne
Country Germany 
Sector Academic/University 
PI Contribution Development of core assays, excluding final in vivo work
Collaborator Contribution In vivo zebrafish model system
Impact PhD thesis, publication in preparation
Start Year 2008
 
Description Festival of the Mind - Fish for Science (CP) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Type Of Presentation Workshop Facilitator
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact A weekend-long hands on event, blending science, art and crafts.
Around 1000 people visited Fish for Science over a 2.5 day period.
We demonstrated the use of zebrafish in medical research using various activities; our zebrafish 'pod' contained microscopes where visitors could view live transgenic embryos; our 'fish tank' was an immersive audio/visual experience, where visitors were surrounded by giant glowing zebrafish; 'Strawberry DNA extraction' introduced visitors to genetics whilst allowing them to do some hands on science; 'Folded Fish' showed visitors how to make an origami fish, and collectively we made a giant mobile; 'Felt Fish' - visitors created a huge quilt of sparkling fish from felt, glitter and sequins; 'Lego Mosaic' - visitors helped build a 4x3m mosaic of a zebrafish out of Lego. Whilst the activities were taking place researchers were on hand to discuss our research with visitors, whilst our 'talking head' videos explained the use of zebrafish in research to those who didn't want to talk to us one-on-one.

The feedback was excellent, with people returning on the following day, and encouraging their friends to come along, visitor numbers increased day on day as word got around. Twitter and Facebook conversations carried on after the event, and visitors to http://fishforscience.com increased by 60%. Visitors of all ages left talking about zebrafish (not just fish) and our feedback board was full of glowing comments.

First time exposure to zebrafish research for many local people, especially families with young children.
Year(s) Of Engagement Activity 2012
 
Description Medicines and Healthcare Regulatory Agency 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact Predicting safety of medicines in human pregnancy: a new era. Working party with MHRA to come up with recommendations for new practices for better prediction of safety of medicines in human pregnancy.
Year(s) Of Engagement Activity 2018,2019
 
Description Schools visits 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Schools
Results and Impact Workshops for teachers, Intensive summer course for post-GSCE students, lectures in Science week

Links forged to local schools
Year(s) Of Engagement Activity 2006,2007,2008,2009