NEUROD1 Is Required for the Early α and β Endocrine Differentiation in the Pancreas

Abstract

Diabetes is a metabolic disease that involves the death or dysfunction of the insulin-secreting β cells in the pancreas. Consequently, most diabetes research is aimed at understanding the molecular and cellular bases of pancreatic development, islet formation, β-cell survival, and insulin secretion. Complex interactions of signaling pathways and transcription factor networks regulate the specification, growth, and differentiation of cell types in the developing pancreas. Many of the same regulators continue to modulate gene expression and cell fate of the adult pancreas. The transcription factor NEUROD1 is essential for the maturation of β cells and the expansion of the pancreatic islet cell mass. Mutations of the Neurod1 gene cause diabetes in humans and mice. However, the different aspects of the requirement of NEUROD1 for pancreas development are not fully understood. In this study, we investigated the role of NEUROD1 during the primary and secondary transitions of mouse pancreas development. We determined that the elimination of Neurod1 impairs the expression of key transcription factors for α- and β-cell differentiation, β-cell proliferation, insulin production, and islets of Langerhans formation. These findings demonstrate that the Neurod1 deletion altered the properties of α and β endocrine cells, resulting in severe neonatal diabetes, and thus, NEUROD1 is required for proper activation of the transcriptional network and differentiation of functional α and β cells.

Milk Exosomal microRNAs: Postnatal Promoters of β Cell Proliferation but Potential Inducers of β Cell De-Differentiation in Adult Life

“…The terminal definitive differentiation into β mature cell identity is achieved by the final activation of pivotal transcription factors, such as NEUROD1, NKX2.2, NKX6, PAX4/6, PDX-1, MAFA, FOXA2, and MNX1 [ 343 , 344 ]. NEUROD1 (also known as BETA2) is a basic helix-loop-helix (bHLH) transcription factor, which is crucial for pancreatic development and is essential for the maturation and differentiation of β cells and insulin production [ 345 ]. NEUROD1, together with PDX-1, ISL1, and MAFA, are key transcription factors regulating insulin synthesis in pancreatic β cells in response to blood glucose [ 346 ].…”

A tissue centric atlas of cell type transcriptome enrichment signatures

“…Synapse related proteins (n=44) included members of the synaptotagmin ( SYT4, 5, 7, 13, 14 ), and glutamate receptor ( GRIA2,3 ) families (Table S3, Tab 2), many of which are reported to be important for pancreatic endocrine cell function e.g., SYT4 (Huang et al, 2018) and SYT13 (Bakhti et al, 2021; Tarquis-Medina et al, 2021), whilst the function of others in this context is not currently known e.g., FRRS1L and NSG1 . Alpha and beta cell co-enriched genes included several encoding for transcription factors involved in islet cell specification, e.g., NKX2-2 , (Churchill et al, 2017), NEUROD1 (Bohuslavova et al, 2021), RFX6 (Soyer et al, 2010), INSM1 (Liang et al, 2021), PAX6 (Hart et al, 2013) and MYT1 (Wang et al, 2007), as well as those with no currently reported function in these cell types, e.g., CELF3 and MYT1L one could speculate such genes likely have a role in neuroendocrine cell function. 91 genes had predicted alpha cell-enrichment, including GCG, TTR and KCNH6 (Figure 3 B, left side); all of which are involved in glucose homeostasis (Noguchi and Huising, 2019; Su et al, 2012; Yang et al, 2018), and other genes with, as yet, no described function in this cell type e.g., SMIM24, CALY and C5orf38 (Figure 3 B, left side).…”

Early Deletion of Neurod1 Alters Neuronal Lineage Potential and Diminishes Neurogenesis in the Inner Ear

“…The focus of this study was to determine the requirements for NEUROD1 in the early neuronal development of the inner ear and processes that are affected by Neurod1 elimination (Figure 11). NEUROD1, a bHLH transcription factor, is an essential factor for the lineage commitment and differentiation in various developmental systems, including gastrointestinal cells (Cherry et al, 2011), pancreas (Romer et al, 2019;Bohuslavova et al, 2021), brain (Miyata et al, 1999;Liu et al, 2000b;Hevner et al, 2006), and neurosensory organs (Liu et al, 2000a;Cherry et al, 2011). The main function of NEUROD1 in neurogenesis and the promotion of neuronal fate is supported by its ability to reprogram other somatic cells into neurons.…”