The long and the short of TRF2 in neurogenesis

Abstract

Gene expression patterns change dramatically during neuronal development. Proliferating cells, including neural stem cells (NSCs), express telomere repeat-binding factor 2 (TRF2), a nuclear protein that associates with telomeric proteins, DNA, and RNA telomeres. In NSCs TRF2 also binds to the transcription regulator REST to facilitate repression of numerous neuron-specific genes, thereby keeping the NSCs in a self-renewing state. Upon neuronal differentiation, TRF2 levels decline, REST-regulated neuronal genes are derepressed, and a short isoform of TRF2 arises (TRF2-S) which localizes in the cytoplasm, associates with different subsets of proteins and transcripts, and mobilizes axonal G-rich mRNAs. We recently identified two RNA-binding proteins, HNRNPH1 and H2 (referred to jointly as HNRNPH due to their high homology), which mediate the alternative splicing of an exon required for the expression of full-length TRF2. As HNRNPH levels decline during neurogenesis, TRF2 abundance decreases and TRF2-S accumulates. Here, we discuss the shared and unique functions of TRF2 and TRF2-S, the distinct subcellular compartment in which each isoform resides, the subsets of proteins and nucleic acids with which each interacts, and the functional consequences of these ribonucleoprotein interactions. This paradigm illustrates the dynamic mechanisms through which splicing regulation by factors like HNRNPH enable distinct protein functions as cells adapt to developmental programs such as neurogenesis.

Keywords: HNRNPH; Neuronal development; REST; RNA-binding proteins; ribonucleoprotein complex; splicing.

Figure 1.

Regulation and impact of alternatively spliced TRF2 and TRF2-S on neurogenesis. (A) Schematic of the alternatively spliced exon 7 giving rise to full length TRF2 (left) and a truncated, short form, TRF2-S (right). In dividing neural cells, the splicing factor HNRNPH1/H2 (HNRNPH) enables a splicing pattern leading to high levels of TRF2. During neurogenesis, HNRNPH levels decline, favoring the formation of the short isoform TRF2-S. (B) The two isoforms share the GAR and TRFH domains, but TRF2 has a nuclear localization signal (NLS), whereas TRF2-S has a nuclear export signal (NES) that mobilizes TRF2-S to the cytoplasm. ‘F’ indicates the TRF2-Phe120 site that interacts with the [F/Y]xL signature motif on hREST4. (C) Schematic representation of the distinct subcellular localizations TRF2 (green ovals) and TRF2-S (green circles) in dividing (left) and post-mitotic (right) neural cells, respectively. The gray shaded boxes summarize the major functions of TRF2 (left) and TRF2-S (right) in different differentiation states.