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PDX1, Neurogenin-3, and MAFA: Critical Transcription Regulators For Zhu et al. Stem Cell Research & Therapy (2017) 8:240 DOI 10.1186/s13287-017-0694-z REVIEW Open Access PDX1, Neurogenin-3, and MAFA: critical transcription regulators for beta cell development and regeneration Yaxi Zhu1,3, Qian Liu2, Zhiguang Zhou3 and Yasuhiro Ikeda1,4* Abstract Transcription factors regulate gene expression through binding to specific enhancer sequences. Pancreas/duodenum homeobox protein 1 (PDX1), Neurogenin-3 (NEUROG3), and V-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MAFA) are transcription factors critical for beta cell development and maturation. NEUROG3 is expressed in endocrine progenitor cells and controls islet differentiation and regeneration. PDX1 is essential for the development of pancreatic exocrine and endocrine cells including beta cells. PDX1 also binds to the regulatory elements and increases insulin gene transcription. Likewise, MAFA binds to the enhancer/promoter region of the insulin gene and drives insulin expression in response to glucose. In addition to those natural roles in beta cell development and maturation, ectopic expression of PDX1, NEUROG3, and/or MAFA has been successfully used to reprogram various cell types into insulin-producing cells in vitro and in vivo, such as pancreatic exocrine cells, hepatocytes, and pluripotent stem cells. Here, we review biological properties of PDX1, NEUROG3, and MAFA, and their applications and limitations for beta cell regenerative approaches. The primary source literature for this review was acquired using a PubMed search for articles published between 1990 and 2017. Search terms include diabetes, insulin, trans-differentiation, stem cells, and regenerative medicine. Keywords: Diabetes, Trans-differentiation, Induced pluripotent stem cells, Embryonic stem cells, Regenerative medicine Background Transcription factors play critical roles in regulating gene Type 1 diabetes mellitus (T1D) is an autoimmune- expression. Ectopic expression of selected transcription mediated disease in which pancreatic beta cells are factors can change, or trans-differentiate, the fate of som- destroyed by the immune system, thus causing life-long atic cells. This process is called cellular reprogramming. dependence on exogenous insulin therapy [1]. This can Reprogramming nonbeta cells into insulin-producing cells lead to hypoglycemic events, injection site complica- potentially offers novel regenerative approaches for T1D tions, insulin resistance, and allergies along with several therapy. There are several transcription factors involved in other issues, while a subset of patients experience diffi- early pancreatic progenitor formation, including pancreas/ culty in controlling fluctuations of blood glucose levels. duodenum homeobox protein 1 (PDX1), forkhead box A2 Islet transplantation has emerged as a promising treat- (FOXA2), and sex determining region Y-box 17 (SOX17). ment option which helps the restoration of glycemic Some transcription factors are critical for endocrine control and protection from severe hypoglycemic events. lineage specification and differentiation, such as Neuro- However, its widespread use has been limited due to in- genin 3 (NEUROG3) and neurogenic differentiation 1 sufficient donor resources, transplant rejection, and the (NEUROD1). Late maturation of beta cells is shown to be necessity for lifelong immune suppression. regulated by factors including V-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MAFA), V-maf mus- * Correspondence: [email protected] culoaponeurotic fibrosarcoma oncogene homolog B 1Department of Molecular Medicine, Mayo Clinic, College of Medicine, 200 First St. SW, Rochester, MN 55905, USA (MAFB), paired box gene 6 (PAX6), and estrogen-related 4Center for Regenerative Medicine, Mayo Clinic, College of Medicine, 200 receptor gamma [2, 3]. Among these transcription factors, First St. SW, Rochester, MN 55905, USA PDX1, NEUROG3, and MAFA are the most extensively Full list of author information is available at the end of the article © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Zhu et al. Stem Cell Research & Therapy (2017) 8:240 Page 2 of 7 explored. They have been repeatedly reported to be able to since it does not coexpress with mature endocrine cell trans-differentiate various types of cells into insulin- hormones including insulin, glucagon, somatostatin, and positive cells, including pancreatic exocrine cells, hepato- pancreatic polypeptide [11]. Forced expression of Neurog3 cytes, intestine cells, gall bladder cells, and stem cells. Here, gene in pancreatic precursor cells in mouse embryos, we focus on these three key beta cell transcription factors under the control of Pdx1 promoter, gives rise to endo- and assess their applications for trans-differentiation of crine cell differentiation, primarily alpha cells, and blocks nonbeta cell types into insulin-producing cells. exocrine development. Conversely, in NEUROG3-deficient mice, four islet cell types (alpha, beta, delta, and pancreatic Biological properties of PDX1, NEUROG3, and MAFA polypeptide cells) and endocrine precursor cells are not PDX1 generated, and neonates die postnatally from diabetes [11]. − PDX1, also known as insulin promoter factor 1, is a Intriguingly, Neurog3+/ heterozygous islets show no no- homeodomain transcription factor. PDX1 expression is table difference from Neurog3+/+ islets in expression of observed as early as embryonic day 8.5 (E8.5) at the 5–6 PDX1, NKX6.1, GLUT2, MAFA, and MAFB on a per cell somite stages in mouse [4] and around gestational week basis [12], suggesting that as long as cells adopt an endo- 4 in human [5]. PDX1 is required for early embryonic crine fate instead of an exocrine fate under NEUROG3 development of the pancreas, as in human study a case stimulation, a relatively low NEUROG3 level per cell does report has shown a 5-year-old female Caucasian suffer- not significantly affect beta cell differentiation. ing from pancreatic agenesis because of a homozygous, Despite these observations, it remains unclear whether single nucleotide deletion within the PDX1 gene [6]. NEUROG3 is absolutely required for beta cell develop- PDX1 is also required for the subsequent differentiation ment in humans. In contrast to mouse studies, all re- of pancreatic lineages. When the expression of PDX1 ported patients with biallelic mutations in NEUROG3 from E11.5 (after the formation of normal pancreatic have functional endocrine cells capable of releasing C- epithelium and ductules) is blocked throughout the par- peptide despite severe enteric anendocrinosis from turition in pregnant mice, the pancreatic development is childhood [13]. All of these cases indicate the presence also arrested as evidenced by the undeveloped pancreatic of insulin-secreting cells, and the reason for this is still remnant consisting of only ducts but no acinar or beta elusive. It is possible that these mutations are hypo- cells [7]. In mature beta cells, depletion and reduction of morphic or null, given the fact that functionality tests PDX1 induces glucose intolerance, which suggests the are mainly limited to their abilities to activate NEU- critical role of PDX1 in maintaining beta cell function ROD1. Nonetheless, it is evident that NEUROG3 is of [7]. This notion is also supported by the identification of great importance for beta cell development and function maturity-onset diabetes of the young 4 (MODY4), one as all biallelic mutated patients present with permanent type of diabetes caused by monogenic defects (heterozy- diabetes, although the threshold level of NEUROG3 re- gous) in the PDX1 gene. In nonobese diabetic (NOD) quirement may be relatively low since all heterozygous mice and human T1D patients, PDX1 autoantibodies are parents are not diabetic. In T1D db/db mice, the NEU- detected, suggesting PDX1 could be an autoantigen for ROG3 expression level is increased markedly [14]. In T1D [8]. In human type 2 diabetes mellitus (T2D), contrast, in human T2D beta cells, no evidence shows PDX1 expression levels of islet beta cells are also com- altered expression of NEUROG3 [9]. In NOD mice, promised [9]. These data highlight the crucial roles of chronic pancreatic immune cell infiltration is correlated PDX1 in early embryonic pancreatic formation, specifi- with the emergence of NEUROG3-positive cells, indicat- cation of different endocrine lineages, and later matur- ing some extent of beta cell neogenesis under auto- ation of beta cell function. immune inflammation [15]. Similar to human T2D beta cells, a human study shows no difference in the percent- NEUROG3 age of NEUROG3 cells (5–10%) in healthy and T1D hu- NEUROG3 is a member of the basic helix–loop–helix man islets [16]. transcription factor family involved in the central ner- vous system and embryonic pancreas development. Dur- MAFA ing the embryonic development of mouse pancreas, MAFA, also known as RIPE3b1, is member of the MAF expression of NEUROG3 is first observed in the dorsal family of basic leucine zipper.
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