Neurog3 gene dosage regulates allocation of endocrine and exocrine cell fates in the developing mouse pancreas

Abstract

The basic helix-loop-helix transcription factor Neurog3 (Neurogenin3 or Ngn3) actively drives endodermal progenitor cells towards endocrine islet cell differentiation during embryogenesis. Here, we manipulate Neurog3 expression levels in endocrine progenitor cells without altering its expression pattern using heterozygosity and a hypomorph. Lowered Neurog3 gene dosage in the developing pancreatic epithelium reduces the overall production of endocrine islet cells without significantly affecting the proportions of various islet cell types that do form. A reduced Neurog3 production level in the endocrine-directed pancreatic progenitor population activates the expression of Neurog3 in an increased number of epithelial progenitors. Yet a significant number of these Neurog3+ cells detected in heterozygous and hypomorphic pancreata, possibly those that express low levels of Neurog3, move on to adopt pancreatic ductal or acinar fates. These data directly demonstrate that achieving high levels of Neurog3 expression is a critical step for endocrine commitment from multipotent pancreatic progenitors. These findings also suggest that a high level of Neurog3 expression could mediate lateral inhibition or other unknown feedback mechanisms to regulate the number of cells that initiate Neurog3 transcription and protein production. The control of Neurog3+ cell number and the Neurog3 threshold-dependent endocrine differentiation mechanism combine to select a specific proportion of pancreatic progenitor cells to adopt the islet cell fate.

Pancreas organogenesis: From bud to plexus to gland

“…By using hypomorphic alleles of Ngn3, Wang et al (2010) demonstrated that the move to Ngn3 HI was necessary for irreversible commitment of cells to the endocrine lineage. Cells with moderate to low levels of Ngn3 can avoid endocrine cell fate commitment and select other pancreatic cell fates.…”

Transgene and islet cell delivery systems using nano-sized carriers for the treatment of diabetes mellitus

“…NEUROG3 can initiate pancreatic islet cells to differentiate and maintain their functions [64,65]. Prophylactic administration of adenoviral vectors designed for expression of NEUROG3 via the tail vain was shown to inhibit the development of diabetes mellitus in a mouse model of diabetes mellitus [12].…”

Transcription factor regulation of pancreatic organogenesis, differentiation and maturation

“…39 Additionally, the threshold of Ngn3 expression is critical for determining endocrine cell fate. 138 High Ngn3 protein expression levels are required to direct pancreatic cell progenitors into the endocrine cell fate whereas low levels of Ngn3 prompt the formation of acinar and duct cells. 138 Hence, endocrine cell fate determination is dependent on the developmental stage and dosage of Ngn3.…”

“…138 High Ngn3 protein expression levels are required to direct pancreatic cell progenitors into the endocrine cell fate whereas low levels of Ngn3 prompt the formation of acinar and duct cells. 138 Hence, endocrine cell fate determination is dependent on the developmental stage and dosage of Ngn3. 138 Interestingly, a recent study supported the hypothesis that Ngn3 C cells constitute a heterogeneous population of unipotent cells each limited to a specific endocrine lineage.…”

“…138 Hence, endocrine cell fate determination is dependent on the developmental stage and dosage of Ngn3. 138 Interestingly, a recent study supported the hypothesis that Ngn3 C cells constitute a heterogeneous population of unipotent cells each limited to a specific endocrine lineage. 139 Ngn3 has been shown to either positively or negatively auto-regulate its own expression.…”