Solving human β‑cell development—what does the mouse say?

1. Solving human β‑cell development—what does the mouse say? Folias, A. E. & Hebrok, M. Nat. Rev. Endocrinol. 10, 253–255 (2014)

2. Introduction • Insulin is a major regulator of systemic glucose and lipid homeostasis that is synthesized & secreted by pancreatic β cells • Autoimmune destruction or loss of function of β cells results in a decreased insulin response and underlies the pathogenesis of type 1 and type 2 diabetes mellitus, respectively • Despite differences in the cause and treatment of the various manifestations of diabetes mellitus, effective therapies depend on understanding the factors that drive β‑cell formation, as well as those that maintain β‑cell function and survival

3. Introduction • Discovery of targets that regulate, preserve or recapitulate these events has proven increasingly critical to the successful design of therapeutic agents • However, it is important to appreciate that finding such targets in a human setting markedly increases the difficulty of this challenge • The study conducted by Flanagan and colleagues has approached this problem strategically, using genetic analysis to systematically determine whether transcription factors critical for β‑cell development in the mouse are conserved in the human

4. Introduction • The ongoing conversation—as far as diabetes mellitus is concerned—centres on a number of key questions • How similar are mouse and human β cells? • Are the development and function of mouse and human β cells controlled by the same mechanisms? • Can the study of genes relevant for β‑cell differentiation and/or function in the mouse help to identify new therapeutic targets in humans?

5. Methods • Compiling information from previously published genetic studies, the researchers generated a list of 29 candidate transcription factors known to be critical for gastrointestinal and pancreatic development in mice • They then used a systematic approach, which was independent of clinical features and guided by linkage analysis, to determine whether these transcription factors are also important in human pancreatic development

6. Methods • They enrolled 147 patients with PNDM from consanguineous pedigrees (that is, blood relatives) to narrow genomic regions identical by descent to increase the likelihood of finding homozygous mutations (‘homozygosity mapping’) • They performed homozygosity and DNA sequence analyses to identify whether the candidate transcription factors were aetiological genes for PNDM among patients diagnosed before 9 months of age

7. Schematic of the study design and key results

8. Results • Mutations in seven genes encoding proteins not involved in transcriptional regulation but known to give rise to the majority of cases of PNDM (ABCC8, EIF2AK3, GCK, INS, KCNJ11, SLC19A2 and SLC2A2) were detected in 110 of the patients • Of the remaining 37 patients, 11 had mutations in candidate transcription factor genes; five of these genes were previously identified human genes known to be involved in PNDM (GLIS3, NEUROD1, PDX1, PTF1A and RFX6) whereas two were novel human genes (MNX1 and NKX2‑2)

9. Results • Interestingly, 26 patients lacked mutations in the non-- transcription factor and candidate transcription factor genes, which suggests that there could be several other important factors affecting development of PNDM that have yet to be found in humans and mice

10. Discussion • The homozygous mutations in 5 of the candidate pancreatic transcription factor genes detected by Flanagan & colleagues supports previously reported mutations detected in patients with PNDM • Specifically, mutations in transcription factor genes resulted in consistent pancreatic phenotypes, including neonatal diabetes mellitus, neonatal diabetes mellitus without exocrine dysfunction or agenesis of the entire pancreas

11. Discussion • The phenotypic differences observed by Flanagan et al. that were dependent upon the severity of the PDX1 mutation (and possibly the MNX1 mutations) emphasize how different base-pair changes can lead to either partial or substantial loss of function • The inability to perform detailed physiological studies in humans limits the information available on how these homozygous inactivating mutations in genes encoding pancreatic transcription factors participate in human organogenesis

12. Conclusion • Overall, the work presented by Flanagan and co-workers lends further support to the notion that key transcription factors critical for β‑cell development are conserved between man and mouse • Their findings validate the use of mouse models for understanding β‑cell development in humans, while highlighting the need for additional systems, such as the generation of β cells from human stem cells, to enable detailed species-specific analyses