Local insulin-like growth factor i expression is essential for Purkinje neuron survival at birth

L. Croci, V. Barili, D. Chia, L. Massimino, R. Van Vugt, G. Masserdotti, R. Longhi, P. Rotwein, G. G. Consalez

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

IGF1, an anabolic and neuroprotective factor, promotes neuronal survival by blocking apoptosis. It is released into the bloodstream by the liver, or synthesized locally by muscles and neural cells, acting in an autocrine or paracrine fashion. Intriguingly, genetic studies conducted in invertebrate and murine models also suggest that an excess of IGF1 signaling may trigger neurodegeneration. This emphasizes the importance of gaining a better understanding of the mechanisms controlling IGF1 regulation and gene transcription. In the cerebellum, Igf1 expression is activated just before birth in a subset of Purkinje cells (PCs). Mice carrying a null mutation for HLH transcription factor EBF2 feature PC apoptosis at birth. We show that Igf1 is sharply downregulated in Ebf2 null PCs starting before the onset of PC death. In vitro, EBF2 binds a conserved distal Igf1 promoter region. The pro-survival PI3K signaling pathway is strongly inhibited in mutant cerebella. Finally, Ebf2 null organotypic cultures respond to IGF1 treatment by inhibiting PC apoptosis. Consistently, wild type slices treated with an IGF1 competitor feature a sharp increase in PC death. Our findings reveal that IGF1 is required for PC survival in the neonatal cerebellum, and identify a new mechanism regulating its local production in the CNS.

Original languageEnglish (US)
Pages (from-to)48-59
Number of pages12
JournalCell Death and Differentiation
Volume18
Issue number1
DOIs
StatePublished - Jan 2011

Fingerprint

Purkinje Cells
Somatomedins
Parturition
Cerebellum
Apoptosis
Cell Death
Null Lymphocytes
Invertebrates
Phosphatidylinositol 3-Kinases
Genetic Promoter Regions
Muscle Cells
Cell Survival
Transcription Factors
Down-Regulation
Mutation
Liver
Genes

Keywords

  • apoptosis
  • ataxia
  • EBF2
  • IGF1
  • Purkinje cells
  • transcription

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

Croci, L., Barili, V., Chia, D., Massimino, L., Van Vugt, R., Masserdotti, G., ... Consalez, G. G. (2011). Local insulin-like growth factor i expression is essential for Purkinje neuron survival at birth. Cell Death and Differentiation, 18(1), 48-59. https://doi.org/10.1038/cdd.2010.78

Local insulin-like growth factor i expression is essential for Purkinje neuron survival at birth. / Croci, L.; Barili, V.; Chia, D.; Massimino, L.; Van Vugt, R.; Masserdotti, G.; Longhi, R.; Rotwein, P.; Consalez, G. G.

In: Cell Death and Differentiation, Vol. 18, No. 1, 01.2011, p. 48-59.

Research output: Contribution to journalArticle

Croci, L, Barili, V, Chia, D, Massimino, L, Van Vugt, R, Masserdotti, G, Longhi, R, Rotwein, P & Consalez, GG 2011, 'Local insulin-like growth factor i expression is essential for Purkinje neuron survival at birth', Cell Death and Differentiation, vol. 18, no. 1, pp. 48-59. https://doi.org/10.1038/cdd.2010.78
Croci, L. ; Barili, V. ; Chia, D. ; Massimino, L. ; Van Vugt, R. ; Masserdotti, G. ; Longhi, R. ; Rotwein, P. ; Consalez, G. G. / Local insulin-like growth factor i expression is essential for Purkinje neuron survival at birth. In: Cell Death and Differentiation. 2011 ; Vol. 18, No. 1. pp. 48-59.
@article{09c377b235be4728aa8ba2d1971472b7,
title = "Local insulin-like growth factor i expression is essential for Purkinje neuron survival at birth",
abstract = "IGF1, an anabolic and neuroprotective factor, promotes neuronal survival by blocking apoptosis. It is released into the bloodstream by the liver, or synthesized locally by muscles and neural cells, acting in an autocrine or paracrine fashion. Intriguingly, genetic studies conducted in invertebrate and murine models also suggest that an excess of IGF1 signaling may trigger neurodegeneration. This emphasizes the importance of gaining a better understanding of the mechanisms controlling IGF1 regulation and gene transcription. In the cerebellum, Igf1 expression is activated just before birth in a subset of Purkinje cells (PCs). Mice carrying a null mutation for HLH transcription factor EBF2 feature PC apoptosis at birth. We show that Igf1 is sharply downregulated in Ebf2 null PCs starting before the onset of PC death. In vitro, EBF2 binds a conserved distal Igf1 promoter region. The pro-survival PI3K signaling pathway is strongly inhibited in mutant cerebella. Finally, Ebf2 null organotypic cultures respond to IGF1 treatment by inhibiting PC apoptosis. Consistently, wild type slices treated with an IGF1 competitor feature a sharp increase in PC death. Our findings reveal that IGF1 is required for PC survival in the neonatal cerebellum, and identify a new mechanism regulating its local production in the CNS.",
keywords = "apoptosis, ataxia, EBF2, IGF1, Purkinje cells, transcription",
author = "L. Croci and V. Barili and D. Chia and L. Massimino and {Van Vugt}, R. and G. Masserdotti and R. Longhi and P. Rotwein and Consalez, {G. G.}",
year = "2011",
month = "1",
doi = "10.1038/cdd.2010.78",
language = "English (US)",
volume = "18",
pages = "48--59",
journal = "Cell Death and Differentiation",
issn = "1350-9047",
publisher = "Nature Publishing Group",
number = "1",

}

TY - JOUR

T1 - Local insulin-like growth factor i expression is essential for Purkinje neuron survival at birth

AU - Croci, L.

AU - Barili, V.

AU - Chia, D.

AU - Massimino, L.

AU - Van Vugt, R.

AU - Masserdotti, G.

AU - Longhi, R.

AU - Rotwein, P.

AU - Consalez, G. G.

PY - 2011/1

Y1 - 2011/1

N2 - IGF1, an anabolic and neuroprotective factor, promotes neuronal survival by blocking apoptosis. It is released into the bloodstream by the liver, or synthesized locally by muscles and neural cells, acting in an autocrine or paracrine fashion. Intriguingly, genetic studies conducted in invertebrate and murine models also suggest that an excess of IGF1 signaling may trigger neurodegeneration. This emphasizes the importance of gaining a better understanding of the mechanisms controlling IGF1 regulation and gene transcription. In the cerebellum, Igf1 expression is activated just before birth in a subset of Purkinje cells (PCs). Mice carrying a null mutation for HLH transcription factor EBF2 feature PC apoptosis at birth. We show that Igf1 is sharply downregulated in Ebf2 null PCs starting before the onset of PC death. In vitro, EBF2 binds a conserved distal Igf1 promoter region. The pro-survival PI3K signaling pathway is strongly inhibited in mutant cerebella. Finally, Ebf2 null organotypic cultures respond to IGF1 treatment by inhibiting PC apoptosis. Consistently, wild type slices treated with an IGF1 competitor feature a sharp increase in PC death. Our findings reveal that IGF1 is required for PC survival in the neonatal cerebellum, and identify a new mechanism regulating its local production in the CNS.

AB - IGF1, an anabolic and neuroprotective factor, promotes neuronal survival by blocking apoptosis. It is released into the bloodstream by the liver, or synthesized locally by muscles and neural cells, acting in an autocrine or paracrine fashion. Intriguingly, genetic studies conducted in invertebrate and murine models also suggest that an excess of IGF1 signaling may trigger neurodegeneration. This emphasizes the importance of gaining a better understanding of the mechanisms controlling IGF1 regulation and gene transcription. In the cerebellum, Igf1 expression is activated just before birth in a subset of Purkinje cells (PCs). Mice carrying a null mutation for HLH transcription factor EBF2 feature PC apoptosis at birth. We show that Igf1 is sharply downregulated in Ebf2 null PCs starting before the onset of PC death. In vitro, EBF2 binds a conserved distal Igf1 promoter region. The pro-survival PI3K signaling pathway is strongly inhibited in mutant cerebella. Finally, Ebf2 null organotypic cultures respond to IGF1 treatment by inhibiting PC apoptosis. Consistently, wild type slices treated with an IGF1 competitor feature a sharp increase in PC death. Our findings reveal that IGF1 is required for PC survival in the neonatal cerebellum, and identify a new mechanism regulating its local production in the CNS.

KW - apoptosis

KW - ataxia

KW - EBF2

KW - IGF1

KW - Purkinje cells

KW - transcription

UR - http://www.scopus.com/inward/record.url?scp=78650173916&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78650173916&partnerID=8YFLogxK

U2 - 10.1038/cdd.2010.78

DO - 10.1038/cdd.2010.78

M3 - Article

VL - 18

SP - 48

EP - 59

JO - Cell Death and Differentiation

JF - Cell Death and Differentiation

SN - 1350-9047

IS - 1

ER -