Haploinsufficiency of Six3 fails to activate Sonic hedgehog expression in the ventral forebrain and causes holoprosencephaly.
Holoprosencephaly (HPE), the most common forebrain malformation, is characterized by an incomplete separation of the cerebral hemispheres. Mutations in the homeobox gene SIX3 account for 1.3% of all cases of human HPE. Using zebrafish-based assays, we have now determined that HPE-associated Six3 mutant proteins function as hypomorphs. Haploinsufficiency of Six3 caused by deletion of one allele of Six3 or by replacement of wild-type Six3 with HPE-associated Six3 mutant alleles was sufficient to recapitulate in mouse models most of the phenotypic features of human HPE. We demonstrate that Shh is a direct target of Six3 in the rostral diencephalon ventral midline (RDVM). Reduced amounts of functional Six3 protein fail to activate Shh expression in the mutant RDVM and ultimately lead to HPE. These results identify Six3 as a direct regulator of Shh expression and reveal a crossregulatory loop between Shh and Six3 in the ventral forebrain.
Geng
Xin
X
Department of Genetics and Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, TN 38105-2794, USA.
Speirs
Christina
C
Lagutin
Oleg
O
Inbal
Adi
A
Liu
Wei
W
Solnica-Krezel
Lilianna
L
Jeong
Yongsu
Y
Epstein
Douglas J
DJ
Oliver
Guillermo
G
D000818:Animals; D017209:Apoptosis; D019521:Body Patterning; D049109:Cell Proliferation; D004027:Diencephalon / Q000002:abnormalities / Q000378:metabolism; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000473:pathology / Q000648:ultrastructure; D004625:Embryo, Nonmammalian / Q000002:abnormalities / Q000473:pathology; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006238:Haploidy; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D016142:Holoprosencephaly / Q000473:pathology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D050505:Mutant Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D016548:Prosencephalon / Q000196:embryology / Q000473:pathology*; D015398:Signal Transduction; D019170:Somites / Q000196:embryology / Q000378:metabolism; D013687:Telencephalon / Q000002:abnormalities / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*; D000097607:Homeobox Protein SIX3
D005136:Eye Proteins; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins; D050505:Mutant Proteins; D009419:Nerve Tissue Proteins; D029961:Zebrafish Proteins; D000097607:Homeobox Protein SIX3; C465570:Shh protein, mouse; C524053:Shha protein, zebrafish