title: Functional dissection of the Pax6 paired domain: Roles in neural tube patterning and peripheral nervous system development.
abstract: During development of the CNS, stem and progenitor cell proliferation, cell fate designation, and patterning decisions are tightly regulated by interdependent networks of key transcriptional regulators. In a genetic approach we analyzed divergent functionality of the PAI and RED sub-domains of the Pax6 Paired domain (PD) during progenitor zone formation, motor and interneuron development, and peripheral connectivity at distinct levels within the neural tube: within the hindbrain, mutation of the PAI sub-domain severely affected patterning of the p3 and pMN domains and establishment of the corresponding motor neurons. Exit point designation of hypoglossal axons was disturbed in embryos harboring either mutations in the PD sub-domains or containing a functional Pax6 Null allele. At brachial spinal levels, we propose a selective involvement of the PAI sub-domain during patterning of ventral p2 and pMN domains, critically disturbing generation of specific motor neuron subtypes and increasing V2 interneuron numbers. Our findings present a novel aspect of how Pax6 not only utilizes its modular structure to perform distinct functions via its paired and homeodomain. Individual sub-domains can exert distinct functions, generating a new level of complexity for transcriptional regulation by one single transcription factor not only in dorso-ventral, but also rostro-caudal neural tube patterning.
authors.affiliation: Institute of Developmental Genetics, Helmholtz Zentrum München - German Research Center for Environmental Health (GmbH), Ingolstädter Landstraße 1, 85764 Neuherberg, Germany.
authors.forename: Rosa-Eva
authors.initials: RE
authors.lastname: Huettl
authors.affiliation: Institute of Developmental Genetics, Helmholtz Zentrum München - German Research Center for Environmental Health (GmbH), Ingolstädter Landstraße 1, 85764 Neuherberg, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Eckstein
authors.affiliation: Institute of Stem Cell Research, Helmholtz Zentrum München - German Research Center for Environmental Health (GmbH), Ingolstädter Landstraße 1, 85764 Neuherberg, Germany.
authors.forename: Tessa
authors.initials: T
authors.lastname: Stahl
authors.affiliation: Institute of Stem Cell Research, Helmholtz Zentrum München - German Research Center for Environmental Health (GmbH), Ingolstädter Landstraße 1, 85764 Neuherberg, Germany.
authors.forename: Stefania
authors.initials: S
authors.lastname: Petricca
authors.affiliation: Institute of Stem Cell Research, Helmholtz Zentrum München - German Research Center for Environmental Health (GmbH), Ingolstädter Landstraße 1, 85764 Neuherberg, Germany.
authors.forename: Jovica
authors.initials: J
authors.lastname: Ninkovic
authors.affiliation: Institute of Stem Cell Research, Helmholtz Zentrum München - German Research Center for Environmental Health (GmbH), Ingolstädter Landstraße 1, 85764 Neuherberg, Germany.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Götz
authors.affiliation: Institute of Developmental Genetics, Helmholtz Zentrum München - German Research Center for Environmental Health (GmbH), Ingolstädter Landstraße 1, 85764 Neuherberg, Germany. Electronic address: andrea.huber@helmholtz-muenchen.de.
authors.forename: Andrea B
authors.initials: AB
authors.lastname: Huber
mesh_terms: D000483:Alleles; D000818:Animals; D001369:Axons / Q000378:metabolism / Q000502:physiology; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D019521:Body Patterning; D019070:Cell Lineage; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000235:genetics; D005136:Eye Proteins / Q000235:genetics* / Q000502:physiology; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D049452:Green Fluorescent Proteins / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics* / Q000502:physiology; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007395:Interneurons / Q000378:metabolism; D051379:Mice; D009046:Motor Neurons / Q000378:metabolism; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics; D054259:Neural Tube / Q000196:embryology*; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics* / Q000502:physiology; D017933:Peripheral Nervous System / Q000196:embryology*; D010641:Phenotype; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000235:genetics* / Q000502:physiology; D012249:Rhombencephalon / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology; D014157:Transcription Factors / Q000235:genetics
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D005136:Eye Proteins; D049452:Green Fluorescent Proteins; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; D012097:Repressor Proteins; D014157:Transcription Factors; C000605732:Pax6 protein, mouse; C490035:Sp8 protein, mouse; C486336:Neurog1 protein, mouse
keywords: Bi-partite paired domain; LMC; MMC; Neural tube patterning; Pax6; Somatic motor neurons; V2 interneurons