Agenesis of the Corpus Callosum Due to Defective Glial Wedge Formation in Lhx2 Mutant Mice.
Establishment of the corpus callosum involves coordination between callosal projection neurons and multiple midline structures, including the glial wedge (GW) rostrally and hippocampal commissure caudally. GW defects have been associated with agenesis of the corpus callosum (ACC). Here we show that conditional Lhx2 inactivation in cortical radial glia using Emx1-Cre or Nestin-Cre drivers results in ACC. The ACC phenotype was characterized by aberrant ventrally projecting callosal axons rather than Probst bundles, and was 100% penetrant on 2 different mouse strain backgrounds. Lhx2 inactivation in postmitotic cortical neurons using Nex-Cre mice did not result in ACC, suggesting that the mutant phenotype was not autonomous to the callosal projection neurons. Instead, ACC was associated with an absent hippocampal commissure and a markedly reduced to absent GW. Expression studies demonstrated strong Lhx2 expression in the normal GW and in its radial glial progenitors, with absence of Lhx2 resulting in normal Emx1 and Sox2 expression, but premature exit from the cell cycle based on EdU-Ki67 double labeling. These studies define essential roles for Lhx2 in GW, hippocampal commissure, and corpus callosum formation, and suggest that defects in radial GW progenitors can give rise to ACC.
Department of Developmental and Cell Biology, School of Biological Sciences, University of California Irvine, Irvine, CA, USA Department of Pathology and Laboratory Medicine, School of Medicine, University of California Irvine, Irvine, CA, USA.
Gregory A
GA
Chinn
Department of Developmental and Cell Biology, School of Biological Sciences, University of California Irvine, Irvine, CA, USA Department of Pathology and Laboratory Medicine, School of Medicine, University of California Irvine, Irvine, CA, USA.
Karla E
KE
Hirokawa
Department of Pathology and Laboratory Medicine, School of Medicine, University of California Irvine, Irvine, CA, USA.
Tony M
TM
Chuang
Department of Pathology and Laboratory Medicine, School of Medicine, University of California Irvine, Irvine, CA, USA.
Cecilia
C
Urbina
Department of Developmental and Cell Biology, School of Biological Sciences, University of California Irvine, Irvine, CA, USA.
Fenil
F
Patel
Department of Developmental and Cell Biology, School of Biological Sciences, University of California Irvine, Irvine, CA, USA.
Jeanette
J
Fong
Department of Pathology and Laboratory Medicine, School of Medicine, University of California Irvine, Irvine, CA, USA.
Nobuo
N
Funatsu
Department of Developmental and Cell Biology, School of Biological Sciences, University of California Irvine, Irvine, CA, USA Department of Pathology and Laboratory Medicine, School of Medicine, University of California Irvine, Irvine, CA, USA Sue and Bill Gross Stem Cell Research Center, University of California Irvine, Irvine, CA, USA.
Edwin S
ES
Monuki
D061085:Agenesis of Corpus Callosum / Q000235:genetics* / Q000473:pathology*; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D019394:Ki-67 Antigen / Q000378:metabolism; D060850:LIM-Homeodomain Proteins / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D019579:Neocortex / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D064231:Nestin / Q000235:genetics; D009457:Neuroglia / Q000473:pathology*; D010523:Peripheral Nervous System Diseases / Q000235:genetics* / Q000473:pathology*; D022661:RNA, Untranslated / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D020825:T-Box Domain Proteins; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D000099260:Empty Spiracles Homeobox Proteins
D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D005904:Glial Fibrillary Acidic Protein; D018398:Homeodomain Proteins; D019394:Ki-67 Antigen; D060850:LIM-Homeodomain Proteins; D009419:Nerve Tissue Proteins; D064231:Nestin; D022661:RNA, Untranslated; D012097:Repressor Proteins; D020825:T-Box Domain Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D000099260:Empty Spiracles Homeobox Proteins; C511143:Bcl11b protein, mouse; C110853:Gt(ROSA)26Sor non-coding RNA, mouse; C489784:Lhx2 protein, mouse; C577485:Nes protein, mouse; C110701:Neurod6 protein, mouse; C492271:Tbr1 protein, mouse
Cre-lox; Lhx2; agenesis of the corpus callosum; glial wedge; mouse