Genetic control of brain morphogenesis through Otx gene dosage requirement

Dario Acampora, Virginia Avantaggiato, Francesca Tuorto, Antonio Simeone

Research output: Contribution to journalArticle

Abstract

Understanding the genetic mechanisms that control patterning of the vertebrate brain represents a major challenge for developmental neurobiology. Previous data suggest that Otx1 and Otx2, two murine homologs of the Drosophila orthodenticle (otd) gene, might both contribute to brain morphogenesis. To gain insight into this possibility, the level of OTX proteins was modified by altering in vivo the Otx gene dosage. Here we report that Otx genes may cooperate in brain morphogenesis and that a minimal level of OTX proteins, corresponding either to one copy each of Otx1 and Otx2, or to only two copies of Otx2, is required for proper regionalization and subsequent patterning of the developing brain. Thus, as revealed by anatomical and molecular analyses, only Otx1(-/-); Otx2(+/-) embryos lacked mesencephalon, pretectal area, dorsal thalamus and showed an heavy reduction of the Ammon's horn, while the metencephalon was dramatically enlarged occupying the mesencencephalic area. In 8.5 days post coitum (d.p.c.) Otx1(-/-) Otx2(+/-) embryos, the expression patterns of mesencephalic-metencephalic (mes-met) markers such as En-1 and Wnt-1 confirmed the early presence of the area fated to give rise to mesencephalon and metencephalon while Fgf-8 transcripts were improperly localized in a broader domain. Thus, in Otx1(-/-) Otx2(+/-) embryos, Fgf-8 misexpression is likely to be the consequence of a reduced level of specification between mes-met primitive neuroepithelia that triggers the following repatterning involving the transformation of mesencephalon into metencephalon, the establishment of an isthmic-like structure in the caudal diencephalon and, by 12.5 d.p.c., the telencephalic expression of Wnt-1 and En-2. Taken together these findings support the existence of a molecular mechanism depending on a precise threshold of OTX proteins that is required to specify early regional diversity between adjacent mes-met territories and, in turn, to allow the correct positioning of the isthmic organizer.

Original languageEnglish
Pages (from-to)3639-3650
Number of pages12
JournalDevelopment
Volume124
Issue number18
Publication statusPublished - 1997

Fingerprint

Metencephalon
Gene Dosage
Morphogenesis
Mesencephalon
Embryonic Structures
Brain
Diencephalon
Telencephalon
Proteins
Neurobiology
Thalamus
Genes
Drosophila
Vertebrates
Hippocampus

Keywords

  • Brain patterning
  • FGF8
  • Isthmic organizer
  • Mouse
  • Otx genes
  • ZLI

ASJC Scopus subject areas

  • Anatomy
  • Cell Biology

Cite this

Acampora, D., Avantaggiato, V., Tuorto, F., & Simeone, A. (1997). Genetic control of brain morphogenesis through Otx gene dosage requirement. Development, 124(18), 3639-3650.

Genetic control of brain morphogenesis through Otx gene dosage requirement. / Acampora, Dario; Avantaggiato, Virginia; Tuorto, Francesca; Simeone, Antonio.

In: Development, Vol. 124, No. 18, 1997, p. 3639-3650.

Research output: Contribution to journalArticle

Acampora, D, Avantaggiato, V, Tuorto, F & Simeone, A 1997, 'Genetic control of brain morphogenesis through Otx gene dosage requirement', Development, vol. 124, no. 18, pp. 3639-3650.
Acampora D, Avantaggiato V, Tuorto F, Simeone A. Genetic control of brain morphogenesis through Otx gene dosage requirement. Development. 1997;124(18):3639-3650.
Acampora, Dario ; Avantaggiato, Virginia ; Tuorto, Francesca ; Simeone, Antonio. / Genetic control of brain morphogenesis through Otx gene dosage requirement. In: Development. 1997 ; Vol. 124, No. 18. pp. 3639-3650.
@article{904febc78c4247e395b313e1e12c3c57,
title = "Genetic control of brain morphogenesis through Otx gene dosage requirement",
abstract = "Understanding the genetic mechanisms that control patterning of the vertebrate brain represents a major challenge for developmental neurobiology. Previous data suggest that Otx1 and Otx2, two murine homologs of the Drosophila orthodenticle (otd) gene, might both contribute to brain morphogenesis. To gain insight into this possibility, the level of OTX proteins was modified by altering in vivo the Otx gene dosage. Here we report that Otx genes may cooperate in brain morphogenesis and that a minimal level of OTX proteins, corresponding either to one copy each of Otx1 and Otx2, or to only two copies of Otx2, is required for proper regionalization and subsequent patterning of the developing brain. Thus, as revealed by anatomical and molecular analyses, only Otx1(-/-); Otx2(+/-) embryos lacked mesencephalon, pretectal area, dorsal thalamus and showed an heavy reduction of the Ammon's horn, while the metencephalon was dramatically enlarged occupying the mesencencephalic area. In 8.5 days post coitum (d.p.c.) Otx1(-/-) Otx2(+/-) embryos, the expression patterns of mesencephalic-metencephalic (mes-met) markers such as En-1 and Wnt-1 confirmed the early presence of the area fated to give rise to mesencephalon and metencephalon while Fgf-8 transcripts were improperly localized in a broader domain. Thus, in Otx1(-/-) Otx2(+/-) embryos, Fgf-8 misexpression is likely to be the consequence of a reduced level of specification between mes-met primitive neuroepithelia that triggers the following repatterning involving the transformation of mesencephalon into metencephalon, the establishment of an isthmic-like structure in the caudal diencephalon and, by 12.5 d.p.c., the telencephalic expression of Wnt-1 and En-2. Taken together these findings support the existence of a molecular mechanism depending on a precise threshold of OTX proteins that is required to specify early regional diversity between adjacent mes-met territories and, in turn, to allow the correct positioning of the isthmic organizer.",
keywords = "Brain patterning, FGF8, Isthmic organizer, Mouse, Otx genes, ZLI",
author = "Dario Acampora and Virginia Avantaggiato and Francesca Tuorto and Antonio Simeone",
year = "1997",
language = "English",
volume = "124",
pages = "3639--3650",
journal = "Development (Cambridge)",
issn = "0950-1991",
publisher = "Company of Biologists Ltd",
number = "18",

}

TY - JOUR

T1 - Genetic control of brain morphogenesis through Otx gene dosage requirement

AU - Acampora, Dario

AU - Avantaggiato, Virginia

AU - Tuorto, Francesca

AU - Simeone, Antonio

PY - 1997

Y1 - 1997

N2 - Understanding the genetic mechanisms that control patterning of the vertebrate brain represents a major challenge for developmental neurobiology. Previous data suggest that Otx1 and Otx2, two murine homologs of the Drosophila orthodenticle (otd) gene, might both contribute to brain morphogenesis. To gain insight into this possibility, the level of OTX proteins was modified by altering in vivo the Otx gene dosage. Here we report that Otx genes may cooperate in brain morphogenesis and that a minimal level of OTX proteins, corresponding either to one copy each of Otx1 and Otx2, or to only two copies of Otx2, is required for proper regionalization and subsequent patterning of the developing brain. Thus, as revealed by anatomical and molecular analyses, only Otx1(-/-); Otx2(+/-) embryos lacked mesencephalon, pretectal area, dorsal thalamus and showed an heavy reduction of the Ammon's horn, while the metencephalon was dramatically enlarged occupying the mesencencephalic area. In 8.5 days post coitum (d.p.c.) Otx1(-/-) Otx2(+/-) embryos, the expression patterns of mesencephalic-metencephalic (mes-met) markers such as En-1 and Wnt-1 confirmed the early presence of the area fated to give rise to mesencephalon and metencephalon while Fgf-8 transcripts were improperly localized in a broader domain. Thus, in Otx1(-/-) Otx2(+/-) embryos, Fgf-8 misexpression is likely to be the consequence of a reduced level of specification between mes-met primitive neuroepithelia that triggers the following repatterning involving the transformation of mesencephalon into metencephalon, the establishment of an isthmic-like structure in the caudal diencephalon and, by 12.5 d.p.c., the telencephalic expression of Wnt-1 and En-2. Taken together these findings support the existence of a molecular mechanism depending on a precise threshold of OTX proteins that is required to specify early regional diversity between adjacent mes-met territories and, in turn, to allow the correct positioning of the isthmic organizer.

AB - Understanding the genetic mechanisms that control patterning of the vertebrate brain represents a major challenge for developmental neurobiology. Previous data suggest that Otx1 and Otx2, two murine homologs of the Drosophila orthodenticle (otd) gene, might both contribute to brain morphogenesis. To gain insight into this possibility, the level of OTX proteins was modified by altering in vivo the Otx gene dosage. Here we report that Otx genes may cooperate in brain morphogenesis and that a minimal level of OTX proteins, corresponding either to one copy each of Otx1 and Otx2, or to only two copies of Otx2, is required for proper regionalization and subsequent patterning of the developing brain. Thus, as revealed by anatomical and molecular analyses, only Otx1(-/-); Otx2(+/-) embryos lacked mesencephalon, pretectal area, dorsal thalamus and showed an heavy reduction of the Ammon's horn, while the metencephalon was dramatically enlarged occupying the mesencencephalic area. In 8.5 days post coitum (d.p.c.) Otx1(-/-) Otx2(+/-) embryos, the expression patterns of mesencephalic-metencephalic (mes-met) markers such as En-1 and Wnt-1 confirmed the early presence of the area fated to give rise to mesencephalon and metencephalon while Fgf-8 transcripts were improperly localized in a broader domain. Thus, in Otx1(-/-) Otx2(+/-) embryos, Fgf-8 misexpression is likely to be the consequence of a reduced level of specification between mes-met primitive neuroepithelia that triggers the following repatterning involving the transformation of mesencephalon into metencephalon, the establishment of an isthmic-like structure in the caudal diencephalon and, by 12.5 d.p.c., the telencephalic expression of Wnt-1 and En-2. Taken together these findings support the existence of a molecular mechanism depending on a precise threshold of OTX proteins that is required to specify early regional diversity between adjacent mes-met territories and, in turn, to allow the correct positioning of the isthmic organizer.

KW - Brain patterning

KW - FGF8

KW - Isthmic organizer

KW - Mouse

KW - Otx genes

KW - ZLI

UR - http://www.scopus.com/inward/record.url?scp=0030730823&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0030730823&partnerID=8YFLogxK

M3 - Article

C2 - 9342056

AN - SCOPUS:0030730823

VL - 124

SP - 3639

EP - 3650

JO - Development (Cambridge)

JF - Development (Cambridge)

SN - 0950-1991

IS - 18

ER -