(MRC DTP) Lost in translation: Understanding the role of activity-dependent transcription in Neurofibromatosis-1

Neurofibromatosis type 1 (NF1) is a commonly inherited neurological disease that affects around 1:2700 individuals1. Around 50-60% of these individuals will have some form of cognitive dysfunction. Consequently, as a monogenic neurodevelopmental disorder with high cognitive dysfunction penetrance, NF1 presents an invaluable avenue in understanding the aetiology of cognitive impairments during development. This cognitive dysfunction has been linked to the aberrant development of a specific population of neurons in the developing brain, namely interneurons2. 

Although interneurons constitute only 20% of all neurons in the brain, they play a vital role in cortical processing. Interneurons are known to modulate the flow of information within cortical circuits. Consequently, any perturbations relating to their development induces impairments in cortical processing and function. Interneurons undergo a protracted development where it ranges from weeks in rodents to months in humans. During this process, interneurons switch from a cell-intrinsically driven development (e.g. through the specific sequential expression of a series of transcription factors) 3, to a more cell-extrinsically driven development. In the latter process, interneurons are known to fine-tune their development by integrating information they received from their local network (e.g. changes in neuronal network activity through the synaptic inputs they receive)4. 

How do interneurons then integrate local information to fine tune their development? By undergoing activity-dependent gene transcription, interneurons react to changes in synaptic inputs by inducing the expression of specific genes. These genes, then go on to be translated into proteins which in turns alter electrophysiological, morphological and connectivity properties. This fine-tuning process during development is vital to ensure that interneurons are correctly incorporated into local neuronal networks5 while learning the appropriate responses to local activity changes. Any perturbations to this adaptive process during development is consequently expected to lead to disruption in cognitive functions. 

In this project, we aim to examine the impact of the NF1 gene mutation on the ability of interneurons to react to changes in local network activity during mouse postnatal development. By combining the expertise and complementing the work done in humans by the Garg lab on NF1 and the Wong lab on interneuron development, we will examine how activity-dependent gene transcription is altered in NF1 mutant mice. We will use state-of-the-art interdisciplinary methodologies such as spatial and single-cell transcriptomics, CRISPR, ex vivo imaging, viral transduction, transgenesis, bioinformatics and animal behaviour to address these questions. Manchester is an internationally recognised centre for its clinical and research work in NF1 and this doctoral project will be embedded within the wider NF1 translational research programme. 

Fong Kuan Wong 

https://www.fongkuanwonglab.com 

Shruti Garg 

https://www.research.manchester.ac.uk/portal/en/researchers/shruti-garg(140592a0-864a-40bc-9015-8b0e0e9011cb)/theses.html 

Eligibility

Applicants must have obtained or be about to obtain a First or Upper Second class UK honours degree, or the equivalent qualifications gained outside the UK, in a relevant discipline.

Before you Apply

Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application.

How to Apply

To be considered for this project you MUST submit a formal online application form - full details on how to apply can be found on the MRC DTP website https://www.bmh.manchester.ac.uk/study/research/mrc-dtp/ 

Your application form must be accompanied by a number of supporting documents by the advertised deadlines. Without all the required documents submitted at the time of application, your application will not be processed and we cannot accept responsibility for late or missed deadlines. Incomplete applications will not be considered. If you have any queries regarding making an application please contact our admissions team [Email Address Removed]

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