Control of Vertebrate Development by MYC

Abstract

The study of MYC has led to pivotal discoveries in cancer biology, induced pluripotency, and transcriptional regulation. In this review, continuing advances in our understanding of the function of MYC as a transcription factor and how its transcriptional activity controls normal vertebrate development and contributes to developmental disorders is discussed. During embryonic development, a great diversity of cell types are rapidly produced concomitant with their organization into the different functional tissues and organ structures needed to sustain life. A common theme underlying higher-order organ development is the initial establishment of stem cells or multipotent progenitor cells at distinct spatial locations. These stem and progenitor populations then respond to local environmental cues by implementing selective activation and/or silencing of specific transcription programs that drive the generation and ordered proliferative expansion of the different cell types and lineages responsible for organ-specific tissue formation. There is intense interest in how these transcriptional programs are established and maintained, both with respect to the signaling pathways and critical transcription factors involved, because their manipulation may permit the in vivo or ex vivo generation of diverse cell types for therapeutic purposes, and because their misregulation appears to be a root cause of diverse cancers and developmental disorders. Prominent among the transcription factors involved are members of the MYC family of proteins, particularly MYC and MYCN.MYC and MYCN, together with the other MYC gene family member, MYCL, encode basic-helix-loop-helix-leucine zipper (BHLHZIP) proteins that function primarily as nuclear transcription factors. However, additional activities of MYC have been identified in the control of DNA replication (Dominguez-Sola et al. 2007), and in the cytoplasm where a cleaved form of MYC that lacks the BHLHZIP region can promote differentiation (Conacci-Sorrell et al. 2010). MYC proteins are best known for their frequent involvement in a great variety of cancers and the ability of ectopic MYC to contribute to pluripotency (Cartwright et al. 2005;Takahashi and Yamanaka 2006;Wernig et al. 2007). The role of MYC family proteins in cancer and induced pluripotency is thought to stem from the appropriation of MYC activities that generally, but not universally, tend to maintain cells in a proliferative state and prevent differentiation. In the context of cancer, the activities

Role of MYC in Medulloblastoma

“…Conditional deletion of Mycn in early neural stem and progenitor cells of this mouse led to profound cerebellum defects, in part owing to the failure to suppress two cyclin-dependent kinase inhibitory proteins (CKIs), p18 Ink4c and p27 Kip1 (Knoepfler et al 2002). Remarkably, these cerebellar defects could be partially rescued by the loss of the two CKIs suggesting that MYCN inhibition of p18 Ink4c and p27 Kip1 expression is required for proper cerebellar development (Knoepfler et al 2002;Zindy et al 2006;Hurlin 2013).…”

Gene regulation in transition

“…Brachyury controls a key developmental process called gastrulation: this produces the body's three major cell layers, and the protein subsequently mediates differentiation of one of these layers, the mesoderm. In animals, both Myc and Brachyury function by binding to enhancers to regulate the transcription of a network of downstream genes 7,8 . Remark ably, SebéPedrós et al found that these downstream gene networks are conserved in animals and Capsaspora.…”

Therapeutic Strategies to Inhibit MYC

“…Indeed, genetic ablation of MYC in mice is embryonic lethal at an early stage of gestation (between days 9.5 and 10.5), with failed hematopoietic development (Davis et al 1993;Hurlin 2013). Although subsequent studies have shown tolerance of tissue-specific MYC loss or downregulation, such as in the liver and small intestine (Bettess et al 2005;Hurlin 2013), concerns remain that pharmacologic inhibition of MYC may feature a narrow therapeutic index.…”

“…Although subsequent studies have shown tolerance of tissue-specific MYC loss or downregulation, such as in the liver and small intestine (Bettess et al 2005;Hurlin 2013), concerns remain that pharmacologic inhibition of MYC may feature a narrow therapeutic index. For example, tolerance of MYC loss in intestinal epithelium could be conferred by compensatory up-regulation of MYCN (Bettess et al 2005;Hurlin 2013), suggesting that selective inhibition of MYC-family isoforms may be required to firmly establish a therapeutic index.…”