Neurobiología Celular y Molecular Versión en español

Subject
The precise development of neuronal connections is essential for the proper function of the nervous system, and aberrant connectivity is associated with neurological disorders. As the regenerative mechanisms induced by nerve injury share many of the cellular and molecular events that control axonal growth and nerve target innervation during development, our understanding of the principles that govern the development of the vertebrate nervous system will help to develop effective treatments for neurological disorders.
The research work in our laboratory is focused on the study of the mechanisms through which neurotrophic factor signaling pathways regulate neuronal migration, differentiation, axon guidance, synaptic maturation and plasticity during nervous system development.

Approach
Our work involve the study of different neuronal population of both the central and peripheral nervous system. Our aim is to identify new molecular mechanisms through which neurotrophic factors control the correct neuronal development. To achieve this, we use different molecular, cellular, biochemical and physiological approaches that involve the use of cell culture techniques, RNAseq assays, microscopy and behavioral assays using different lines of transgenic mice.

Advances
1-Understand the mechanisms by which neuronal precursors differentiate into mature neurons
The balance between the factors that lead to proliferation and differentiation of cortical neuronal precursors determines the correct development of the cortex and that is why the study of the factors that control this process is relevant. We showed that glial-cell derived neurotrophic factor (GDNF) and its receptor GFRa1are expressed in the embryonic cortex during the period of cortical neurogenesis, inhibiting the self-renewal capacity of precursors and promoting neuronal differentiation. Whereas GDNF leads to decreased proliferation of cultured cortical precursor cells, ablation of GFRa1 in glutamatergic cortical precursors increases their proliferation. Consistent with this, analysis of GFRa1-deficient mice showed an increase in the number of dividing cells during cortical development and a reduction in the differentiation of mature neurons. Taken together, these results indicate that GDNF/GFRa1 signaling plays an essential role in the regulation of cortical progenitors.
2- Identification of transcriptional programs and signaling pathways involved in neuronal connectivity and regeneration processes.
The correct neuronal differentiation throughout the development of the nervous system is an essential process in the establishment of synaptic connections. Intrinsic and extrinsic factors participate in this process. Among them, the neurotrophins plays an important role. Using transcriptomic assays, we identified 2 transcriptional factors of the Pea3 family, called Etv4 and Etv5, which are induced by neurotrophic factors (NGF and BDNF), and which act as mediators of the biological effects triggered by them in different neuronal populations of the peripheral and central nervous system.
We describe that NGF stimulation in the distal compartments of sensory neurons is sufficient to induce the expression of these two transcription factors that participate in axonal growth of the peripheral system and that are necessary for the detection of external sensory stimuli.
3-Analysis of the role of the neurotrophic factor, GDNF in synapse formation
Glial-derived neurotrophic factor (GDNF) was initially described as a survival and growth factor for dopaminergic neurons. Later similar effects were described in other neurons of the central and peripheral nervous system. In recent years, our group has described an essential role of this factor and its receptor GFRa1 in synapse formation,a cting as an transsynaptic adhesion complex. Analysis of animals deficient for the GDNF receptor, GFRa1, shows a reduction in dendritic complexity and a decrease in synaptic contacts in hippocampal pyramidal neurons and in new hippocampal neurons born in adults. These observations open new paths to explore the physiological functions of this complex in the establishment of synaptic contacts in other neuronal populations and its relevance in nervous system diseases.