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Insulin in Neurogenesis

Presented byAROGUNDADE,

Tolulope Timothy(08/46KA015)LECTURER: Dr. O.B. Akinola

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Outline IntroductionInsulin and PropertiesInsulin Receptor and PathwaysInsulin in Neuronal MigrationInsulin in Neurodegenerative DisordersConclusions

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Introduction

Photo credits: med.unc.edu Paperstock.org Funzim.com

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Insulin and Properties

Insulin is a hormone that helps to regulate the storage of glycogen in the liver and accelerates oxidation of sugar in cells.

Insulin is essential to maintaining brain function.

(Ghasemi et al., 2013)

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Where it is Produced

The hormone insulin is secreted by the β cells of the Islets of Langerhans in the pancreas.

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Insulin Receptor

The insulin receptor is a receptor tyrosine kinase well studied with regard to its function in the regulation of peripheral glucose metabolism.

Recent studies in neuronal cell culture suggest that insulin receptor signaling regulates several neuronal functions, including spine density and neurite growth.

(Choi et al., 2005)

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Structure of the Insulin receptor

(De Meyts et al., 2002)

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Accessory Molecules

Insulin receptor require accessory molecules known as insulin receptor substrates (IRSs) - for example IRS1-4- to engage multiple downstream signaling (Withers, 2001).

Two major cellular signaling pathways, phosphoinositide-3 kinase (PI3K)/Akt and the Ras/mitogen-activated protein kinase (MAPK).

(Schulingkamp et al., 2000)

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(De Meyts et al., 2002)

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Insulin Receptor Signaling Functions

Brain insulin receptor signaling reportedly plays diverse roles in the CNS; -including regulation of synaptic plasticity.

(Huang et al., 2003) -dendritic outgrowth.

(Chen et al., 2003) -and involvement in neuronal survival, life span , learning and memory, and neurological disorders.

(Steen et al., 2005)

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Insulin in Neuronal Migration

Nonautonomous Regulation of Neuronal Migration by Insulin Signaling, DAF-16/FOXO, and PAK-1.

Objective-To demonstrate that insulin/IGF-1-PI3K signaling pathway modulates the activity of the DAF-16/FOXO transcription factor to regulate the anterior migrations of the hermaphrodite-specific neurons (HSNs) during embryogenesis of C. elegans.

(Lisa et al., 2013)

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Results

(Lisa et al., 2013)

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Summary

DAF-16 activity is required in the hypodermal tissue of C. elegans to nonautonomously promote the HSN migrations and that this activity relies on the release of insulin/IGF-1-mediated inhibition of DAF-16.

(Lisa et al., 2013)

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Another Case Study

Ethanol, Insulin/IGF Signaling and Neuronal Migration

-To establish that chronic gestational exposure to ethanol impairs neuronal migration in the developing brain, and that this effect of ethanol is associated with reduced expression and function of a critical target gene, aspartyl- aparaginyl beta-hydroxylase (AAH), which has a demonstrated role in cell motility.

Objective

(De La Monte et al., 2013/2014)

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Result Ethanol exposure causes insulin and insulin-like growth factor (IGF) resistance, inhibiting downstream signaling through PI3K-Akt, Erk MAPK, and Cdk-5 pathways that regulate AAH mRNA.

(De La Monte et al., 2013/2014)

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Insulin and Neurological

DiseasesAlthough the role that the insulin receptor may play in these disorders is still a puzzle, enhanced brain insulin receptor signaling has been used to treat schizophrenia patients early in the mid-20th century (Doroshow, 2007) .

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Conclusion

Insulin could be said to function as a motogen and stop signal cue in neuronal migration.

Insulin signaling is required for viability, metabolism, and synapse formation in the CNS.

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ReferencesChiu SL, Chen CM, Cline HT: Insulin receptor signaling regulates synapse number, dendritic plasticity, and circuit function in vivo. Neuron 2008, 58:708-719.Choi J, Ko J, Racz B, Burette A, Lee JR, Kim S, Na M, Lee HW, Kim K, Weinberg RJ, Kim E:Regulation of dendritic spine morphogenesis by insulin receptor substrate 53, a downstream effector of Rac1 and Cdc42 small GTPases. J Neurosci 2005, 25:869-879.De Meyts P, Whittaker J: Structural biology of insulin and IGF1 receptors: implications for drug design. Nat Rev Drug Discov 2002, 1:769-783.Kanezaki Y, Obata T, Matsushima R, Minami A, Yuasa T, Kishi K, Bando Y, Uehara H, Izumi K, Mitani T, Matsumoto M, Takeshita Y, Nakaya Y, Matsumoto T, Ebina Y: K(ATP) channel knockout mice crossbred with transgenic mice expressing a dominant-negative form of human insulin receptor have glucose intolerance but not diabetes. Endocr J 2004, 51:133-144. PubMed Abstract | Publisher Full TextWhite MF: Insulin signaling in health and disease. Science 2003, 302:1710-1711. PubMed Abstract | Publisher Full Text Withers DJ: Insulin receptor substrate proteins and neuroendocrine function. Biochem Soc Trans 2001, 29:525-529.

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Thank You For Listening