Increased levels of apoptosis in the prefusion neural folds underlie the craniofacial disorder, Treacher Collins syndrome.

Treacher Collins syndrome (TCS) is an autosomal dominant disorder of human craniofacial development that results from loss-of-function mutations in the gene TCOF1. Although this gene has been demonstrated to encode the nucleolar phosphoprotein treacle, the developmental mechanism underlying TCS remains elusive, particularly as expression studies have shown that the murine orthologue, Tcof1, is widely expressed. To investigate the molecular pathogenesis of TCS, we replaced exon 1 of Tcof1 with a neomycin-resistance cassette via homologous recombination in embryonic stem cells. Tcof1 heterozygous mice die perinatally as a result of severe craniofacial anomalies that include agenesis of the nasal passages, abnormal development of the maxilla, exencephaly and anophthalmia. These defects arise due to a massive increase in the levels of apoptosis in the prefusion neural folds, which are the site of the highest levels of Tcof1 expression. Our results demonstrate that TCS arises from haploinsufficiency of a protein that plays a crucial role in craniofacial development and indicate that correct dosage of treacle is essential for survival of cephalic neural crest cells.

[1]  J. Beckmann,et al.  Human-mouse differences in the embryonic expression patterns of developmental control genes and disease genes. , 2000, Human molecular genetics.

[2]  Joe C. Adams,et al.  Eya1-deficient mice lack ears and kidneys and show abnormal apoptosis of organ primordia , 1999, Nature Genetics.

[3]  M. Depew,et al.  Dlx5 regulates regional development of the branchial arches and sensory capsules. , 1999, Development.

[4]  G. Merlo,et al.  Craniofacial, vestibular and bone defects in mice lacking the Distal-less-related gene Dlx5. , 1999, Development.

[5]  Ivana Peluso,et al.  minifly, A Drosophila Gene Required for Ribosome Biogenesis , 1999, The Journal of cell biology.

[6]  R. Axton,et al.  Missense mutations in the most ancient residues of the PAX6 paired domain underlie a spectrum of human congenital eye malformations. , 1999, Human molecular genetics.

[7]  E. Giordano,et al.  A Drosophila Gene Required for Ribosome Biogenesis , 1999 .

[8]  R. Shiang,et al.  The Treacher Collins syndrome (TCOF1) gene product, treacle, is targeted to the nucleolus by signals in its C-terminus. , 1998, Human molecular genetics.

[9]  Hailan Zhang,et al.  An Early Phase of Embryonic Dlx5 Expression Defines the Rostral Boundary of the Neural Plate , 1998, The Journal of Neuroscience.

[10]  M. Dixon,et al.  Mutations in the Treacher Collins syndrome gene lead to mislocalization of the nucleolar protein treacle. , 1998, Human molecular genetics.

[11]  J. Weissenbach,et al.  Clustering of mutations responsible for branchio-oto-renal (BOR) syndrome in the eyes absent homologous region (eyaHR) of EYA1. , 1997, Human molecular genetics.

[12]  E. Jabs,et al.  Mouse TCOF1 is expressed widely, has motifs conserved in nucleolar phosphoproteins, and maps to chromosome 18. , 1997, Biochemical and biophysical research communications.

[13]  J. Rubenstein,et al.  Inductive interactions direct early regionalization of the mouse forebrain. , 1997, Development.

[14]  J. Rubenstein,et al.  Role of the Dlx homeobox genes in proximodistal patterning of the branchial arches: mutations of Dlx-1, Dlx-2, and Dlx-1 and -2 alter morphogenesis of proximal skeletal and soft tissue structures derived from the first and second arches. , 1997, Developmental biology.

[15]  R. Shiang,et al.  Sequence analysis, identification of evolutionary conserved motifs and expression analysis of murine tcof1 provide further evidence for a potential function for the gene and its human homologue, TCOF1. , 1997, Human molecular genetics.

[16]  M. Lovett,et al.  TCOF1 gene encodes a putative nucleolar phosphoprotein that exhibits mutations in Treacher Collins Syndrome throughout its coding region. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[17]  P. Scambler,et al.  Identification of the complete coding sequence and genomic organization of the Treacher Collins syndrome gene. , 1997, Genome research.

[18]  M. Dixon,et al.  The mutational spectrum in Treacher Collins syndrome reveals a predominance of mutations that create a premature-termination codon. , 1997, American journal of human genetics.

[19]  J. Weissenbach,et al.  A human homologue of the Drosophila eyes absent gene underlies Branchio-Oto-Renal (BOR) syndrome and identifies a novel gene family , 1997, Nature Genetics.

[20]  S. Scherer,et al.  Mutations in the human Sonic Hedgehog gene cause holoprosencephaly , 1996, Nature Genetics.

[21]  P. Beachy,et al.  Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function , 1996, Nature.

[22]  R. Hennekam,et al.  Treacher Collins syndrome may result from insertions, deletions or splicing mutations, which introduce a termination codon into the gene. , 1996, Human molecular genetics.

[23]  M. Dixon,et al.  Prenatal diagnosis in Treacher Collins syndrome using combined linkage analysis and ultrasound imaging. , 1996, Journal of medical genetics.

[24]  R. Behringer,et al.  Prenatal folic acid treatment suppresses acrania and meroanencephaly in mice mutant for the Cart1 homeobox gene , 1996, Nature Genetics.

[25]  R. Winter.  What's in a face? , 1996, Nature Genetics.

[26]  J. Wasmuth,et al.  Positional cloning of a gene involved in the pathogenesis of Treacher Collins syndrome , 1996, Nature Genetics.

[27]  J. Rubenstein,et al.  Null mutation of Dlx-2 results in abnormal morphogenesis of proximal first and second branchial arch derivatives and abnormal differentiation in the forebrain. , 1995, Genes & development.

[28]  R. Fässler,et al.  Consequences of lack of beta 1 integrin gene expression in mice. , 1995, Genes & development.

[29]  P. Tam,et al.  Cranial paraxial mesoderm and neural crest cells of the mouse embryo: co-distribution in the craniofacial mesenchyme but distinct segregation in branchial arches. , 1995, Development.

[30]  C. Cremers,et al.  The Treacher Collins syndrome. A clinical, radiological, and genetic linkage study on two pedigrees. , 1995, Archives of otolaryngology--head & neck surgery.

[31]  J. Rossant,et al.  Notch1 is required for the coordinate segmentation of somites. , 1995, Development.

[32]  K. Eto,et al.  The contribution of both forebrain and midbrain crest cells to the mesenchyme in the frontonasal mass of mouse embryos. , 1994, Developmental biology.

[33]  Richard L. Maas,et al.  PAX6 gene dosage effect in a family with congenital cataracts, aniridia, anophthalmia and central nervous system defects , 1994, Nature Genetics.

[34]  R. Balling,et al.  The role of Pax-1 in axial skeleton development. , 1994, Development.

[35]  T. Matsuo,et al.  A mutation in the Pax-6 gene in rat small eye is associated with impaired migration of midbrain crest cells , 1993, Nature Genetics.

[36]  G. Blobel,et al.  Nopp 140 shuttles on tracks between nucleolus and cytoplasm , 1992, Cell.

[37]  L. Strong,et al.  Positional cloning and characterization of a paired box- and homeobox-containing gene from the aniridia region , 1991, Cell.

[38]  G. Saunders,et al.  Mouse Small eye results from mutations in a paired-like homeobox-containing gene , 1991, Nature.

[39]  W. Webster,et al.  Teratogens and craniofacial malformations: relationships to cell death. , 1988, Development.

[40]  K. Sulik,et al.  Mandibulofacial dysostosis (Treacher Collins syndrome): a new proposal for its pathogenesis. , 1987, American journal of medical genetics.

[41]  M. Wiley,et al.  Effects of retinoic acid on the development of the facial skeleton in hamsters: early changes involving cranial neural crest cells. , 1983, Acta anatomica.

[42]  Robert J. Gorlin,et al.  Syndromes of the Head and Neck , 1976 .

[43]  D. Poswillo.  The pathogenesis of the treacher Collins syndrome (Mandibulofacial dysostosis) , 1975 .

[44]  H. Nadler,et al.  Mandibulo-facial dysostosis. (Treacher-Collins syndrome). , 1967, American journal of diseases of children.

[45]  S. Rovin,et al.  MANDIBULOFACIAL DYSOSTOSIS, A FAMILIAL STUDY OF FIVE GENERATIONS. , 1964, The Journal of pediatrics.