ARISTIA-II NeuroNetwk Project

Unraveling the role of a novel gene regulatory network in neural development

A long standing question in biological sciences is how cell diversity and specification patterns are generated during tissue development. In the central nervous system (CNS) of vertebrates a large variety of cell types are specified from a pool of highly plastic neural stem/progenitor cells (NSCs) via a combined action of extrinsic morphogenetic cues and intrinsic gene regulatory networks. The current view in the field suggests that these regulatory networks act to subdivide the neural tube into defined progenitor domains with restricted developmental potentials and establish distinct differentiation programs in the neurons and glial cells that emerge from each domain (i.e. Figure 1). Failure of NSCs to make the correct specification choice at the appropriate time can result in severe developmental deficits, malformations, neurodegenerative diseases or cancers. Despite the wealth of information on the morphogens’ action in NSCs, little is known about the intrinsic gene regulatory networks that define neuronal and glial cell identity. The long term aim of our group is to understand the fundamental gene regulation networks that control NSC differentiation and sub-type specification in health and disease. Elucidation of these networks should provide insights into the basic principles involved in the nervous system formation, as well as practical information for applications of regenerative medicine and treatments of CNS related diseases and traumas.

Figure 1. Embryonic mouse neural tube was stained for nuclei (blue), Prox1 (red) and Hdac3 (red)

For long time, it was thought that these networks are mainly based on cross-regulatory interactions between transcription factors. However, current results strongly indicate that long non-coding RNAs (lncRNAs), a newly discovered class of regulatory RNAs, constitute key components of such networks. Understanding the involvement of this family of molecules in organogenesis could revolutionize the basic principles of developmental and stem cell biology. Towards this long term goal, our group is interested in understanding the molecular mechanisms that connect transcription factors and lncRNAs in coherent cross-regulatory networks to control CNS development. This proposal is focused on delineating the function and cross-regulatory interactions of a network consisted of: a) Prox1, a well studied homeobox transcription factor with a key/established role in neural development, b) Ariel, (previously known as AK142161), a lncRNA transcribed from the Prox1 gene locus in an anti-parallel manner (Figure 2) and c) NR5A2 (LRH1), an orphan nuclear receptor that regulates transcription and directly interacts with Prox1. Thus, the main aims of the proposed project are to elucidate: a) the involvement of this network in CNS development, b) the molecular mechanism by which each component regulates the properties of NSCs, and c) the links and molecular mechanisms that inter-connect these genes to form a cross-regulatory network.

Figure 2. Schematic representation of the Prox1-Ariel genomic locus in mouse chromosome 1

Members of the Group:

Panagiotis Politis, Principal Investigator

Valeria Kaltezioti, Lab manager

Maximilianos Elkouris, Post-Doctoral fellow

Athanasios Stergiopoulos, PhD Student

Daphne Antoniou, PhD Student

Penelope Fouka, PhD Student

Elpinickie Ninou, PhD Student

Dimitris Gkikas, PhD Student

Tina Tsamboula, MSc Student

Angelica Mesa, MSc Student

Thomas Giotis, MSc Student