Protein identified as key element in brain development

The Molecular and Developmental Neurobiology research group at the University of Lleida (UdL) and the Institute for Research in Biomedicine of Lleida (IRBLleida) has identified a protein, called Rnd3 or RhoE, as a fundamental element in brain development and in the establishment of important neuronal connections. Rnd3/RhoE belongs to the RhoGTPase family, which act as biochemical "switches" of cell function. This finding will allow future research to continue understanding the functioning of the nervous system and the circuits that control and coordinate simple tasks such as the movement of a limb, to much more complex ones such as emotions, consciousness, the capacity for abstraction or memory. The research is published in the Journal of Neurochemistry.

"Understanding the logic of neuronal circuits and how they perform their function is undoubtedly the most important frontier of knowledge in biomedical research in the 21st century," explained Joaquim Egea, professor Serra Hunter of the UdL and head of the Molecular and Developmental Neurobiology group. When the functionality of these circuits is compromised by genetic causes, trauma or a neurodegenerative process (Parkinson's or Alzheimer's), the consequences can be dramatic, Egea specified. "To illustrate the extreme complexity and magnitude of this challenge, we have to think that we are talking about a structure like our brain, made up of some 69,000 million neurons and 1014 connections between them," the researcher explained.

The research, which also involved the collaboration of staff from the Department of Animal Medicine and Surgery of the Faculty of Veterinary Medicine at the CEU Cardenal Herrera University in Valencia, was carried out by studying genetically manipulated mice that lacked the Rnd3/RhoE protein and in which it was observed that they had severe defects in several important axonal connections in the brain.

The basic structure of neuronal circuits is established and organised during embryonic development in the womb. At these stages, young neurons establish connections between themselves by growing an appendage, the axon, thus facilitating communication between different regions of the nervous system. The study of this process, known as "axonal guidance", allows us to better understand how our nervous system is formed and how it functions. It is known, for example, that during axonal guidance, axons are exposed to environmental molecules that are recognised by specific receptors located on the surface of their cell membrane, which direct and instruct (guide) their movement in a very precise way until they connect with their target cell. "Although most of these molecules and their receptors have been identified, the intracellular mechanisms that take place in response to these stimuli are still largely unknown," explains Egea. For this reason, this discovery is important, as mutations in some members of these families of RhoGTPase proteins have been associated with some diseases that affect the development of the nervous system in humans.

The research has been possible thanks to several grants from the Spanish Ministry of Science and Innovation (PGC2018-101910-B-I00, BFU2010-1805, BFU 2013-48563-P, BES-2014-067618, SAF2013-49176-C2-1-R), the European Union (FP7-PEOPLE-2011-CIG,) and the SANTANDER-FUSP Programme.  

Article:

Marfull‐Oromí, P, Fleitas, C, Zammou, B, et al. Genetic ablation of the Rho GTPase Rnd3 triggers developmental defects in internal capsule and the globus pallidus formation. J Neurochem. 2021; 00: 1- 20. https://doi.org/10.1111/jnc.15322