© Riccardo Cassiani-Ingoni / Photo Researchers, Inc.
Destroying proteins may seem like an odd way of promoting new growth, but this is exactly what happens in neurogenesis. Certain controlling factors are permanently turned off by the ubiquitin proteasome system (UPS), allowing neuronal growth to proceed. Without this tight control of neurogenic genes, a cell can become predisposed to cancer or end up in a developmental dead end.
The UPS controls the degradation of unwanted proteins in the cell by marking target proteins with chains of ubiquitin. Proteins labeled with polyubiquitin chains are recognized and broken down by the proteasome, a large protein complex found in all eukaryotes. Proteasomes degrade abnormal and misfolded proteins, and are involved in the regulation of the stress response, the cell cycle, and cell differentiation.
Are these multiple ubiquitinated proteins providing an overlapping fail-safe mechanism?
The UPS works in three stages. First, ubiquitin is linked covalently to the E1 ubiquitin-activating enzyme. Second, ubiquitin is transferred to the E2 ubiquitin-conjugation enzyme. Finally, it is attached to a specific substrate destined for degradation by one of over 600 E3 ubiquitin ligases.
The largest group of E3 ligases is the really interesting new gene (RING) family of ligases. Recent studies revealed that this family, as well as smaller families of ligases, plays critical roles in the regulation of neurogenesis.
Sealing cell fate
One way a cell’s fate is determined is through epigenetic modifications that restrict expression of appropriate genes. In neuronal precursor cells, the RE-1 silencing transcription factor (REST) binds to genes involved in neurogenesis, and with several other proteins, recruits histone deacetylases (HDACs) to silence the genes. The HDAC modifications cause histones to tightly wrap around those stretches of DNA, making the genes inaccessible to transcription and suppressing the neuronal fate. With those genes normally suppressed by REST, how do neuronal precursor cells escape silencing and initiate neurogenesis?
Thomas Westbrook and colleagues at the Harvard Medical School found that REST is marked for degradation in embryonic stem cells.1 The E3 ligase that specifically targets REST consists of several adaptor proteins, including one of the RING proteins. Therefore, controlled destruction of REST by the UPS prevents the recruitment of HDACs, allowing the unencumbered transcription of neuronal genes.
A second study investigated the ubiquitination of the transcription factor N-Myc during neurogenesis. Normally, N-Myc maintains the proliferation of pluripotent precursor cells in the nervous system, perpetuating self-renewal without differentiation. Researchers found that the E3 ligase, Huwe1, containing a HECT (‘homolog to E6AP C-terminus’) domain triggers polyubiquitination and subsequent degradation of N-Myc. Suppressing self-renewal via Huwe1–induced breakdown of N-Myc pushes the progenitor cell one step closer to differentiation into neurons.2
In a third example of UPS-mediated neurogenesis, researchers noticed that the E3 ligase TRIM32 is up-regulated in the neuronal progenitor cells, but not in the pluripotent stem cells that produce them. Like Huwe1, TRIM32 degrades c-Myc, another transcription factor that promotes self-renewal over differentiation.3
The degradation of Myc family members appears to be a recurring theme in cells that differentiate along the neuronal lineage. It remains to be seen what precise role each E3 ligase plays at each stage of the development and function of the nervous system. How each of these E3 ligases is regulated in neural precursor cells is another unanswered question; are these multiple ubiquitinated proteins providing an overlapping fail-safe mechanism, for example, or do these distinct signaling pathways interact to produce neural stem cells progeny with different specialized functions?
The role of additional E3 ligases in neurogenesis, as well as a deeper understanding of the ones we already know about, is critical for understanding disease pathogenesis. For example, deregulation of neurogenesis is thought to play a critical role in the formation and progression of brain tumors.4 Studying the UPS involvement in regulating the transition from multipotent stem cell to neuron could also identify potential therapeutic targets to stimulate formation of new nerve cells, raising the possibility of exciting new targets for Parkinson’s and other neurodegenerative disorders.
This article is an adaptation of an article published in F1000 Biology Reports, a publication of the Faculty of 1000. For the full-length version, click here. F1000 Biology consists of more than 2,000 leading biologists (Faculty Members) who select and review the most important published papers in their respective fields (Faculties). The next two pages describe recent selections from various Faculties.