Neuronal differentiation and its physiological and pharmacological modulation: role of the trancription factor REST

Nervous system development relies on a complex signalling network to engineer the orderly transitions that lead to the acquisition of a neural cell fate (Ballas and Mandel, 2005). Progression from the non neuronal pluripotent stem cell to a restricted neural lineage is characterized by distinct patterns of gene expression, particularly the restriction of neuronal gene expression to neurons (Ballas and Mandel, 2005).

The Repressor Element 1 Silencing Transcription Factor (REST), also known as the Neuron-restrictive Silencer Factor (NRSF), plays a pivotal role in such a context as it maintains transcriptional silencing of a range of neuronal genes in differentiated non-neuronal cells, as well as in un-differentiated neuronal cells during early lineage commitment in neurogenesis.

REST, in fact, was originally discovered as a transcriptional repressor of a large number of primarily terminal neuronal differentiation genes in non-neuronal cells and neuronal stem cells (NSCs); its transcription is generally blocked as NSCs undergo differentiation (Majumder, 2006), so that neuronal development can occur properly.

However, REST is expressed in some differentiated neurons and, when bound to a double-stranded small RNA, it is able to function also as an activator of its target gene transcription (Majumder et al., 2006), thus suggesting for REST a complex regulatory function in both embryonic and adult neuronal differentiation.

In addition, REST dysfunction has been implicated in diverse diseases ranging from Down’s syndrome to cardiomyopathy and cancer, emphasising its importance also as a master regulator of normal gene expression programs (Coulson, 2005).

REST contains a DNA-binding domain and two distinct repressor domains, which can interact with several cellular repressor complexes, including huntintin protein (Htt) in the cytoplasm and mSin3A, histone deacetylases (HDACs), N-Cor, CoREST, histone H3-K9 methyltransferase G9a (HMTase), histone H3-K4 demethylase LSD1 (HDMase), DNA methyl transferase 1 (DNMT1), DNA-methyl-CpG-binding protein-2 (MeCP2) and chromatin remodelling complexes SWI/SNF in the nucleus (Fig. 1.1).   Therefore REST serves as a giant communication hub for the cell, having a variety of roles in normal development as well as causing several abnormalities when deregulated (Majumder, 2006).

We are investigating how neuronal differentiation is determined in human and rat cellular systems: particularly, we are studying IGF-I-, phorbol esthers- and retinoids-induced differentiation of SH-SY5Y human neuroblastoma cells and H-19/7 rat hippocampal neurons. Our goal is to unravel cellular and molecular processes responsible for proper neuronal fate acquisition as well as for aberrant differentiation occurring in tumors.

Normal development and abnormal development are, in fact, two sides of the same coin.