title: RING1 proteins contribute to early proximal-distal specification of the forelimb bud by restricting Meis2 expression.
abstract: Polycomb group (PcG) proteins play a pivotal role in silencing developmental genes and help to maintain various stem and precursor cells and regulate their differentiation. PcG factors also regulate dynamic and complex regional specification, particularly in mammals, but this activity is mechanistically not well understood. In this study, we focused on proximal-distal (PD) patterning of the mouse forelimb bud to elucidate how PcG factors contribute to a regional specification process that depends on developmental signals. Depletion of the RING1 proteins RING1A (RING1) and RING1B (RNF2), which are essential components of Polycomb repressive complex 1 (PRC1), led to severe defects in forelimb formation along the PD axis. We show that preferential defects in early distal specification in Ring1A/B-deficient forelimb buds accompany failures in the repression of proximal signal circuitry bound by RING1B, including Meis1/2, and the activation of distal signal circuitry in the prospective distal region. Additional deletion of Meis2 induced partial restoration of the distal gene expression and limb formation seen in the Ring1A/B-deficient mice, suggesting a crucial role for RING1-dependent repression of Meis2 and likely also Meis1 for distal specification. We suggest that the RING1-MEIS1/2 axis is regulated by early PD signals and contributes to the initiation or maintenance of the distal signal circuitry.
authors.affiliation: Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences (IMS), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan nayuta.yakushiji@epfl.ch haruhiko.koseki@riken.jp.
authors.forename: Nayuta
authors.initials: N
authors.lastname: Yakushiji-Kaminatsui
authors.affiliation: Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences (IMS), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan CREST, Japan Science and Technology Agency, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan KAST, Project on Health and Anti-aging, 3-25-13 Tonomachi, Kawasaki-ku, Kawasaki 210-0821, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kondo
authors.affiliation: Laboratory for Integrative Genomics, RIKEN IMS, 1-7-22 Suehirocho, Tsurumi-ku, Yokohama 230-0045, Japan.
authors.forename: Takaho A
authors.initials: TA
authors.lastname: Endo
authors.affiliation: Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences (IMS), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan CREST, Japan Science and Technology Agency, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Koseki
authors.affiliation: Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences (IMS), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan CREST, Japan Science and Technology Agency, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan KAST, Project on Health and Anti-aging, 3-25-13 Tonomachi, Kawasaki-ku, Kawasaki 210-0821, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Kondo
authors.affiliation: Laboratory for Integrative Genomics, RIKEN IMS, 1-7-22 Suehirocho, Tsurumi-ku, Yokohama 230-0045, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Ohara
authors.affiliation: Centro de Investigaciones Biológicas, Department of Cellular and Molecular Biology, Ramiro de Maeztu 9, Madrid 28040, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Vidal
authors.affiliation: Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences (IMS), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan CREST, Japan Science and Technology Agency, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan nayuta.yakushiji@epfl.ch haruhiko.koseki@riken.jp.
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Koseki
mesh_terms: D000818:Animals; D047369:Chromatin Immunoprecipitation; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D005260:Female; D005552:Forelimb / Q000196:embryology*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D063150:Polycomb Repressive Complex 1 / Q000235:genetics / Q000378:metabolism*; D011247:Pregnancy; D000072516:Retinoic Acid 4-Hydroxylase; D014212:Tretinoin / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D018398:Homeodomain Proteins; C102641:Mrg1 protein, mouse; C489936:Prrx1 protein, mouse; D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; D000072516:Retinoic Acid 4-Hydroxylase; D063150:Polycomb Repressive Complex 1; C489840:Ring1 protein, mouse; C489842:Rnf2 protein, mouse; D044767:Ubiquitin-Protein Ligases
keywords: Meis; Mouse limb development; Polycomb; Proximal-distal specification; RING1