Neuronal Generation and Degeneration in Vertebrates

Work in our laboratory is aimed at understanding mechanisms integrating cell cycle progression versus cell cycle exit and differentiation, which result in the control of neuron generation in the central nervous system. The deregulation of such mechanisms and their association with neurodegenerative pathologies is also an interest of our group. To fulfil these objectives, a multidisciplinary approach based in morphological, biochemical, molecular and cellular techniques is used. As model systems, we use both mouse and chick embryos.

1) Expression and function of proneural and neurogenic genes along the cell cycle in neural precursors
We have demonstrated that the mechanisms regulating neuronal production are linked to the cell cycle machinery (Murciano et al., 2002; Cisneros et al., 2008). We aim to unravel the molecular basis for such a connection by analyzing the regulation of neurogenic gene promoters and the stability of their mRNAs, as well as the posttranslational modifications of proneural gene products. We have demonstrated that HuR is necessary for the stabilization of Delta 1 mRNA (García-Domínguez et al., 2011). We have also demonstrated that Delta1 expression ahead of the neurogenic wavefront optimizes neurogenesis by preventing perturbations in lateral inhibition and in wavefront progression (Formosa-Jordán et al., 2012; 2013).

2) Signal transduction of the neurotrophin receptor p75 and the cell cycle
We aim to study the contribution of a novel mechanism used by p75 to transduce signals (Frade, 2005; López-Sánchez et al., 2007a), based on the nuclear translocation of its intracellular domain in response to neurotrophin binding, leading to cell cycle re-entry (Frade, 2000), somatic tetraploidy in neurons (Morillo et al., 2010; Morillo et al., 2012), and apoptosis (Santos et al., 2012) during the development of the nervous system as well as during neurodegeneration.

3) Functional and pathological aspects of neuronal tetraploidy
The normal nervous system contains subpopulations of tetraploid neurons in a number of neural tissues (Morillo et al., 2010; López-Sánchez et al., 2011; López-Sánchez and Frade, 2013). These neurons are functional (López-Sánchez and Frade, 2013). We are interested in defining the molecular mechanisms involved in their generation (Morillo et al., 2010; Morillo et al., 2012) as well as their subsequent maintenance (Ovejero-Benito and Frade, 2013; 2015). The implication of neuronal tetraploidization in normal physiology (Frade, 2010) and putative epigenetic changes (Patiño-Parrado et al., 2017) is also an interest of our Lab.
In this regard, we are primarily interested in:

• Characterizing the molecular mechanisms inducing somatic tetraploidization in adult neurons, focusing our analysis in the E2F4 transcription factor and its putative phosphorylation by p38MAPK. We have a patent for the use of mutant forms of E2F4 as a therapeutical agent against Alzheimer’s disease.
• Studying the morphological and functional changes in neurons undergoing somatic tetraploidization, including compensatory mechanisms for gene expression and possible epigenetic changes occurring in these neurons.
• Verifying the participation of somatic tetraploidization in neurodegenerative diseases, focusing on Alzheimer’s disease. This work is performed in the framework of the biotech company Tetraneuron S.L., a spin-off from our laboratory. Finally, we are also interested in analyzing the endogenous capacity of neurons to undergo cell cycle progression (Frade and Ovejero-Benito, 2015; Walton et al., 2019), and the pathophysiological effects of neuronal hyperploidization (Barrio-Alonso et al., 2018).

Most relevant methodology:
To carry out our research we use a multidisciplinary approach based on molecular biology, biochemistry, cellular biology, immunohistochemistry, and flow cytometry.

Citations of the Group