RAC1 function in neurodevelopment and neurodevelopmental disease

RAC1 regulates a variety of essential cellular functions including cell motility and proliferation1,2,3. We recently showed that RAC1 is critical for normal human development by discovering a novel neurodevelopmental syndrome caused by mutations in the RAC1 gene4,5. In this project, we will explore the role of RAC1 in neurodevelopment and investigate how RAC1 dysfunction results in impaired development. The principle aims of this project are to -

Identify the key neurodevelopmental roles for RAC1.

Understand the molecular and cellular mechanisms by which RAC1 mutations identified in patients lead to abnormal neuronal development and function. Use knowledge gained to devise strategies for future treatment of developmental diseases caused by RAC1 dysfunction. Experimentally, the project will involve -

1. Computational bioinformatics analysis to identify and classify new patients with RAC1 mutations.

2. Cell culture and biochemistry experiments to study molecular characteristics and cellular effects of RAC1 mutations found in patients.

3. Modelling the role of RAC1 and effects of disease mutations on neurodevelopment in Drosophila (fruit fly) and Xenopus (frog) model organisms.

This is a truly inter-disciplinary project led by a team composed of basic scientists and a clinical academic who will bring complementary areas of expertise. Each of the supervisors have active research programmes and this will expose the student to a breadth and depth of biomedical research that is usually very difficult to find in a project set in a single laboratory.

The project will equip the student with a range of versatile skills including bioinformatic analysis of human genome/exome sequences, cell culture, modelling human disease in model organisms and cloning/transgenesis techniques such as CRISPR. The skills and knowledge provided by project will provide a solid foundation for a future career in developmental biology, precision medicine, translational medicine or neuroscience.

References: 1. Duquette, P. M. & Lamarche-Vane, N. Rho GTPases in embryonic development. Small GTPases 5 e972857 (2014). 2. Ng, J. et al. Rac GTPases control axon growth, guidance and branching. Nature 416 442-447 (2002).

3. Woolner S, Jacinto A, Martin P. The small GTPase Rac plays multiple roles in epithelial sheet fusion--dynamic studies of Drosophila dorsal closure. Dev Biol. 282 163-73. (2005)

4. Reijnders MRF, Ansor NM, Kousi M, Yue WW, Tan PL, Clarkson K, Clayton-Smith J, Corning K, Jones JR, Lam WWK, Mancini GMS, Marcelis C, Mohammed S, Pfundt R, Roifman M, Cohn R, Chitayat D; Deciphering Developmental Disorders Study, Millard TH, Katsanis N, Brunner HG,

Banka S. RAC1 Missense Mutations in Developmental Disorders with Diverse Phenotypes. Am. J. Hum. Genet. (2017) 101 466-477.

5. Banka S, Bennington A, Baker MJ, Rijckmans E, Clemente GD, Ansor NM, Sito H, Prasad P, Anyane-Yeboa K, Badalato L, Dimitrov B, Fitzpatrick D, Hurst ACE, Jansen AC, Kelly MA, Krantz I, Rieubland C, Ross M, Rudy NL, Sanz J, Stouffs K, Xu ZL, Malliri A, Kazanietz MG, Millard TH. Activating RAC1 variants in the switch II region cause a developmental syndrome and alter neuronal morphology. Brain. 2022 doi: 10.1093/brain/awac049. Epub ahead of print. PMID: 35139179.