Neogenesis of β-Cells in Adult BETA2/NeuroD-Deficient Mice

Huang, Hsiang-Po; Chu, Khoi; Némoz-Gaillard, Eric; Elberg, Dorit; Tsai, Ming‐Jer

doi:10.1210/mend.16.3.0784

Cited by 27 publications

(9 citation statements)

References 39 publications

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“…This finding is analogous to neuroD, which is essential for beta cell formation in pancreas and also for transcriptional regulation of insulin in the developed pancreas (52,53).…”

Section: Molecules That Form Emotional Memory Are Decreased In Neurod2-mentioning

confidence: 56%

The dosage of the neuroD2 transcription factor regulates amygdala development and emotional learning

Lin

Hansen

Wang

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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The amygdala is centrally involved in formation of emotional memory and response to fear or risk. We have demonstrated that the lateral and basolateral amygdala nuclei fail to form in neuroD2 null mice and neuroD2 heterozygotes have fewer neurons in this region. NeuroD2 heterozygous mice show profound deficits in emotional learning as assessed by fear conditioning. Unconditioned fear was also diminished in neuroD2 heterozygotes compared to wild-type controls. Several key molecular regulators of emotional learning were diminished in the brains of neuroD2 heterozygotes including Ulip1, ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, and GABA A receptor. Thus, neuroD2 is essential for amygdala development and genes involved in amygdala function are altered in neuroD2-deficient mice.basic helix-loop-helix ͉ haploinsufficiency T he amygdala is an almond-shaped brain structure that integrates emotional learning and other emotional responses such as fear perception. The role of the amygdala in fear perception and response was established through lesioning studies in animals and confirmed through positron emission tomography and functional magnetic resonance imaging in normal human subjects and in schizophrenic patients with deficits in fear processing (1-9).We previously reported that neuroD2-null mice on a mixed genetic background are indistinguishable from littermates at birth, but fail to thrive and die within weeks of birth. Before death, nullizygous mice develop ataxia, seizures, cerebellar degeneration, and growth retardation. NeuroD2 heterozygotes appear normal as adults, but have reduced seizure threshold and mild ataxia. We observed aggressive behavior between neuroD2 heterozygotes, which prompted us to evaluate the function and structure of the amygdala and related limbic system brain regions that control aggression, fear, and other emotions. Unconditioned fear (also referred to as anxiety or risk perception) is the response to environmental cues that signal danger. The basolateral amygdala and ventral subiculum of hippocampus are involved in unconditioned fear responses; however, the neuronal circuitry and molecular mechanisms are poorly understood (10).In contrast to unconditioned fear, the neurochemical and molecular basis of emotional learning related to conditioned fear are being elucidated through studies that evaluate fear conditioning in the context of pharmacologic or genetic manipulation of neurotransmitter receptors and second messengers. Fear conditioning involves coupling a neutral conditioned stimulus (CS) such as an audible tone with a noxious unconditioned stimulus (US) such as foot shock and observing that after training and rest periods, that the CS alone is sufficient to elicit behavioral (e.g., freezing) and autonomic responses (11,12). During the training and rest period, the lateral amygdala acquires and consolidates short-and long-term memory that associates the conditioned and unconditioned stimuli through a process known as emotional learning.The acquisition phas...

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“…This finding is analogous to neuroD, which is essential for beta cell formation in pancreas and also for transcriptional regulation of insulin in the developed pancreas (52,53).…”

Section: Molecules That Form Emotional Memory Are Decreased In Neurod2-mentioning

confidence: 56%

The dosage of the neuroD2 transcription factor regulates amygdala development and emotional learning

Lin

Hansen

Wang

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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“…Indeed MafB, cMaf as well as NeuroD1/Beta2 are all involved in ␣ cell development and differentiation (17,18,20). Functionally, MafB-or cMaf-deficient mice show an important reduction in both insulin-and glucagon-positive cells throughout development indicating a significant role of MafB and cMaf in differentiation, replication, and/or survival of endocrine precursor cells (17,20).…”

Section: Discussionmentioning

confidence: 99%

Pax6 Controls the Expression of Critical Genes Involved in Pancreatic α Cell Differentiation and Function*

Gosmain

Marthinet

Cheyssac

et al. 2010

Journal of Biological Chemistry

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The paired box homeodomain Pax6 is crucial for endocrine cell development and function and plays an essential role in glucose homeostasis. Indeed, mutations of Pax6 are associated with diabetic phenotype. Importantly, homozygous mutant mice for Pax6 are characterized by markedly decreased ␤ and ␦ cells and absent ␣ cells. To better understand the critical role that Pax6 exerts in glucagon-producing cells, we developed a model of primary rat ␣ cells. To study the transcriptional network of Pax6 in adult and differentiated ␣ cells, we generated Pax6-deficient primary rat ␣ cells and glucagon-producing cells, using either specific siRNA or cells expressing constitutively a dominantnegative form of Pax6. In primary rat ␣ cells, we confirm that Pax6 controls the transcription of the Proglucagon and processing enzyme PC2 genes and identify three new target genes coding for MafB, cMaf, and NeuroD1/Beta2, which are all critical for Glucagon gene transcription and ␣ cell differentiation. Furthermore, we demonstrate that Pax6 directly binds and activates the promoter region of the three genes through specific binding sites and that constitutive expression of a dominant-negative form of Pax6 in glucagon-producing cells (InR1G9) inhibits the activities of the promoters. Finally our results suggest that the critical role of Pax6 action on ␣ cell differentiation is independent of those of Arx and Foxa2, two transcription factors that are necessary for ␣ cell development. We conclude that Pax6 is critical for ␣ cell function and differentiation through the transcriptional control of key genes involved in glucagon gene transcription, proglucagon processing, and ␣ cell differentiation.

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“…NeuroD1 is a basic helix-loop-helix transcription factor that is essential for pancreatic and neuronal embryonic development and postnatal functions (13)(14)(15)(16)(17)(18). In the developing pancreas, NeuroD1 is detected as early as e9.5 in the early glucagon-producing populations (14).…”

mentioning

confidence: 99%

“…At this time the null mice display reduced insulin production and significantly decreased ␤ cell mass due to apoptosis (14). Interestingly, on certain genetic backgrounds, NeuroD1 null mice can survive postnatally with only mild hyperglycemia (13). These findings suggest that NeuroD1 plays a predominant role in the maintenance of functional ␤ cells after they have formed, although it has been suggested that the absence of an earlier phenotype may be due to redundancy with other NeuroD family members (20).…”

mentioning

confidence: 99%

Cooperative Transcriptional Regulation of the Essential Pancreatic Islet Gene NeuroD1 (Beta2) by Nkx2.2 and Neurogenin 3

Anderson

Torres

Solomon

et al. 2009

Journal of Biological Chemistry

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Nkx2.2 and NeuroD1 are two critical regulators of pancreatic ␤ cell development. Nkx2.2 is a homeodomain transcription factor that is essential for islet cell type specification and mature ␤ cell function. NeuroD1 is a basic helix-loop-helix transcription factor that is critical for islet ␤ cell maturation and maintenance. Although both proteins influence ␤ cell development directly downstream of the endocrine progenitor factor, neurogenin3 (Ngn3), a connection between the two proteins in the regulation of ␤ cell fate and function has yet to be established. In this study, we demonstrate that Nkx2.2 transcriptional activity is required to facilitate the activation of NeuroD1 by Ngn3. Furthermore, Nkx2.2 is necessary to maintain high levels of NeuroD1 expression in developing mouse and zebrafish islets and in mature ␤ cells. Interestingly, Nkx2.2 regulates NeuroD1 through two independent promoter elements, one that is bound and activated directly by Nkx2.2 and one that appears to be regulated by Nkx2.2 through an indirect mechanism. Together, these findings suggest that Nkx2.2 coordinately activates NeuroD1 with Ngn3 within the endocrine progenitor cell and also plays a role in the maintenance of NeuroD1 expression to regulate ␤ cell function in the mature islet. Collectively, these findings further define the conserved regulatory networks involved in islet ␤ cell formation and function.The pancreas is an intricate organ composed of exocrine tissue that secretes digestive enzymes into pancreatic ducts, and the endocrine islets of Langerhans that produce the metabolic hormones insulin, glucagon, somatostatin, pancreatic polypeptide, and ghrelin. The different pancreatic cell lineages arise during the critical developmental events referred to as the primary and secondary transitions (Ref. 1; reviewed in Ref. 2). The primary transition occurs between embryonic day (e) 8.5 and e11.5 2 and encompasses the initial patterning and specification of the pancreatic endoderm, which originates from the foregut. The secondary transition is the critical stage between e12.5 and e15.5 when endocrine and exocrine progenitors expand and a large second wave of differentiation is initiated. The secondary transition also marks an increase in the expression and/or relocalization of a number of transcription factors that are important in pancreatic development, including Pdx1, Ptf1a, Ngn3, Nkx2.2, NeuroD1, Pax4, Pax6, and Nkx6.1 (reviewed in Ref. 3). A large number of studies of these transcription factors have yielded a timeline of gene expression and determined which cell lineages are regulated by each transcription factor (2-7). Notably, temporal and spatial changes in many of the transcription factor expression profiles can re-program a progenitor or precursor cell to alter, prevent, or initiate endocrine differentiation (3, 8 -12). The cumulative findings of these studies have illustrated that the regulation of islet cell differentiation depends on complex relationships between the transcriptional regulatory cascades. These regulato...

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Neogenesis of β-Cells in Adult BETA2/NeuroD-Deficient Mice

Cited by 27 publications

References 39 publications

The dosage of the neuroD2 transcription factor regulates amygdala development and emotional learning

The dosage of the neuroD2 transcription factor regulates amygdala development and emotional learning

Pax6 Controls the Expression of Critical Genes Involved in Pancreatic α Cell Differentiation and Function*

Cooperative Transcriptional Regulation of the Essential Pancreatic Islet Gene NeuroD1 (Beta2) by Nkx2.2 and Neurogenin 3

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