Abstract
The transcription factor Otx2 is required to determine mesencephalic versus metencephalic (cerebellum/pons) territory during embryogenesis. This function of Otx2 primarily involves positioning and maintaining the mid-hindbrain organizer at the border between midbrain and anterior hindbrain. Otx2 expression is maintained long after this organizer is established. We therefore generated conditional mutants of Otx2 using the Cre/loxP system to study later roles during rostral brain development. For inactivation of Otx2 in neuronal progenitor cells, we crossed Otx2(flox/flox) animals with Nestin-Cre transgenic animals. In Nestin-Cre/+; Otx2(flox/flox) embryos, Otx2 activity was lost from the ventral midbrain starting at embryonic day 10.5 (E10.5). In these mutant embryos, the mid-hindbrain organizer was properly positioned at E12.5, although Otx2 is absent from the midbrain. Hence, the Nestin-Cre/+; Otx2(flox/flox) animals represent a novel mouse model for studying the role of Otx2 in the midbrain, independently of abnormal development of the mid-hindbrain organizer. Our data demonstrate that Otx2 controls the development of several neuronal populations in the midbrain by regulating progenitor identity and neurogenesis. Dorsal midbrain progenitors ectopically expressed Math1 and generate an ectopic cerebellar-like structure. Similarly, Nkx2.2 ectopic expression ventrally into tegmentum progenitors is responsible for the formation of serotonergic neurons and hypoplasia of the red nucleus in the midbrain. In addition, we discovered a novel role for Otx2 in regulating neurogenesis of dopaminergic neurons. Altogether, these results demonstrate that Otx2 is required from E10.5 onward to regulate neuronal subtype identity and neurogenesis in the midbrain.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Age Factors
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Animals
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Animals, Newborn
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Basic Helix-Loop-Helix Transcription Factors / metabolism
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Body Patterning*
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Bromodeoxyuridine / metabolism
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Cell Count / methods
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Cell Differentiation / genetics
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Cell Differentiation / physiology
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Dopamine / metabolism
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Embryo, Mammalian
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Embryonic Induction / genetics
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Fibroblast Growth Factor 8 / metabolism
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Gene Expression Regulation, Developmental / genetics
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Gene Expression Regulation, Developmental / physiology*
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Homeobox Protein Nkx-2.2
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism
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Immunohistochemistry / methods
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In Situ Hybridization / methods
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In Situ Nick-End Labeling / methods
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Intermediate Filament Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism
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Kruppel-Like Transcription Factors / metabolism
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Membrane Proteins / metabolism
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Mesencephalon / cytology*
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Mesencephalon / embryology
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Mesencephalon / growth & development
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Mice
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Mice, Transgenic
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Nerve Tissue Proteins / genetics
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Nestin
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Neurons / physiology*
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Organizers, Embryonic / metabolism
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Otx Transcription Factors / deficiency
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Otx Transcription Factors / physiology*
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Patched Receptors
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Receptors, Cell Surface
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Serotonin / genetics
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Serotonin / metabolism
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Wnt1 Protein / metabolism
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Zebrafish Proteins
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Zinc Finger Protein GLI1
Substances
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Atoh1 protein, mouse
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Basic Helix-Loop-Helix Transcription Factors
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Fgf8 protein, mouse
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Gbx2 protein, mouse
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Gli1 protein, mouse
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Homeobox Protein Nkx-2.2
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Homeodomain Proteins
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Intermediate Filament Proteins
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Intracellular Signaling Peptides and Proteins
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Kruppel-Like Transcription Factors
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Membrane Proteins
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Nerve Tissue Proteins
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Nes protein, mouse
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Nestin
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Nkx2-2 protein, mouse
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Otx Transcription Factors
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Otx2 protein, mouse
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Patched Receptors
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Receptors, Cell Surface
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Transcription Factors
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Wnt1 Protein
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Wnt1 protein, mouse
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Zebrafish Proteins
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Zinc Finger Protein GLI1
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nkx2.2b protein, zebrafish
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Fibroblast Growth Factor 8
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Serotonin
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Bromodeoxyuridine
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Dopamine