title: Six3 dosage mediates the pathogenesis of holoprosencephaly.
abstract: Holoprosencephaly (HPE) is defined as the incomplete separation of the two cerebral hemispheres. The pathology of HPE is variable and, based on the severity of the defect, HPE is divided into alobar, semilobar, and lobar. Using a novel hypomorphic Six3 allele, we demonstrate in mice that variability in Six3 dosage results in different HPE phenotypes. Furthermore, we show that whereas the semilobar phenotype results from severe downregulation of Shh expression in the rostral diencephalon ventral midline, the alobar phenotype is caused by downregulation of Foxg1 expression in the anterior neural ectoderm. Consistent with these results, in vivo activation of the Shh signaling pathway rescued the semilobar phenotype but not the alobar phenotype. Our findings show that variations in Six3 dosage result in different forms of HPE.
authors: Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
authors: Xin
authors: X
authors: Geng
authors: Center for Vascular and Developmental Biology, Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, IL 60611, USA.
authors: Sandra
authors: S
authors: Acosta
authors: Department of Genetics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Oleg
authors: O
authors: Lagutin
authors: Center for Vascular and Developmental Biology, Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, IL 60611, USA.
authors: Hyea Jin
authors: HJ
authors: Gil
authors: Center for Vascular and Developmental Biology, Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, IL 60611, USA guillermo.oliver@northwestern.edu.
authors: Guillermo
authors: 0000-0003-3984-7615
authors: G
authors: Oliver
mesh_terms: D000818:Animals; D002460:Cell Line; D054022:Cerebrum / Q000002:abnormalities / Q000196:embryology*; D004027:Diencephalon / Q000196:embryology / Q000378:metabolism; D004475:Ectoderm / Q000378:metabolism; D005136:Eye Proteins / Q000235:genetics*; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D057809:HEK293 Cells; D057895:Haploinsufficiency / Q000235:genetics*; D053823:Hedgehog Proteins / Q000096:biosynthesis / Q000378:metabolism; D016142:Holoprosencephaly / Q000235:genetics* / Q000473:pathology; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction / Q000502:physiology; D000097607:Homeobox Protein SIX3
chemical_list: D005136:Eye Proteins; D051858:Forkhead Transcription Factors; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D000097607:Homeobox Protein SIX3; C489565:Foxg1 protein, mouse; C465570:Shh protein, mouse
keywords: Forebrain; Gene dosage; Holoprosencephaly; Mouse; Six3; Transcription factor