Mice deficient in the candidate tumor suppressor gene Hic1 exhibit developmental defects of structures affected in the Miller-Dieker syndrome.

HIC1 is a candidate tumor suppressor gene which is frequently hypermethylated in human tumors, and its location within the Miller-Dieker syndrome's critical deletion region at chromosome 17p13.3 makes it a candidate gene for involvement in this gene deletion syndrome. To study the function of murine Hic1 in development, we have created Hic1 -deficient mice. These animals die perinatally and exhibit varying combinations of gross developmental defects throughout the second half of development, including acrania, exencephaly, cleft palate, limb abnormalities and omphalocele. These findings demonstrate a role for Hic1 in the development of structures affected in the Miller-Dieker syndrome, and provide functional evidence to strengthen its candidacy as a gene involved in this disorder.

[1]  S. Hirohashi,et al.  DNA hypermethylation at the D17S5 locus in non-small cell lung cancers: its association with smoking history. , 1997, Cancer research.

[2]  Richard Axel,et al.  Visualizing an Olfactory Sensory Map , 1996, Cell.

[3]  H. Saumweber,et al.  The enhancer of position-effect variegation of Drosophila, E(var)3-93D, codes for a chromatin protein containing a conserved domain common to several transcriptional regulators. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[4]  K. Chew,et al.  Loss of heterozygosity and p53 gene mutations in breast cancer. , 1994, Cancer research.

[5]  J. Crawley,et al.  Impaired learning and motor behavior in heterozygous Pafah1b1 (Lis1) mutant mice. , 1999, Learning & memory.

[6]  Y. Yatabe,et al.  Detailed deletion mapping suggests the involvement of a tumor suppressor gene at 17p13.3, distal to p53, in the pathogenesis of lung cancers , 1998, Oncogene.

[7]  D. Ledbetter,et al.  Isolation of a Miller–Dicker lissencephaly gene containing G protein β-subunit-like repeats , 1993, Nature.

[8]  K. Steel,et al.  Normal hearing in Splotch (Sp/+), the mouse homologue of Waardenburg syndrome type 1 , 1992, Nature genetics.

[9]  W. Dobyns,et al.  Syndromes with lissencephaly. I: Miller-Dieker and Norman-Roberts syndromes and isolated lissencephaly. , 1984, American journal of medical genetics.

[10]  D. Leprince,et al.  The BTB/POZ domain: a new protein-protein interaction motif common to DNA- and actin-binding proteins. , 1995, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[11]  R. Treisman,et al.  The POZ domain: a conserved protein-protein interaction motif. , 1994, Genes & development.

[12]  D. Ledbetter,et al.  Graded reduction of Pafah1b1 (Lis1) activity results in neuronal migration defects and early embryonic lethality , 1998, Nature Genetics.

[13]  Y. Jan,et al.  lola encodes a putative transcription factor required for axon growth and guidance in Drosophila. , 1994, Development.

[14]  C. Thummel,et al.  The Drosophila Broad-Complex plays a key role in controlling ecdysone-regulated gene expression at the onset of metamorphosis. , 1993, Development.

[15]  S. Baylin,et al.  DNA hypermethylation is associated with 17p allelic loss in neural tumors. , 1993, Cancer research.

[16]  L. Lania,et al.  Repression of transcriptional activity at a distance by the evolutionarily conserved KRAB domain present in a subfamily of zinc finger proteins. , 1994, Nucleic acids research.

[17]  V. Bedian,et al.  Differential expression of Broad-Complex transcription factors may forecast tissue-specific developmental fates during Drosophila metamorphosis. , 1994, Development.

[18]  S. Weitzman,et al.  Methylation of the HIC-1 candidate tumor suppressor gene in human breast cancer , 1998, Oncogene.

[19]  D. Withers,et al.  The Drosophila Broad-Complex encodes a family of related proteins containing zinc fingers. , 1991, Genetics.

[20]  S. Baylin,et al.  p53 activates expression of HIC-1, a new candidate tumour suppressor gene on 17p13.3 , 1995, Nature Genetics.

[21]  Philippe Soriano,et al.  Insertional mutagenesis by retroviruses and promoter traps in embryonic stem cells. , 1993, Methods in enzymology.

[22]  S. Beckendorf,et al.  The Broad‐Complex directly controls a tissue‐specific response to the steroid hormone ecdysone at the onset of Drosophila metamorphosis. , 1994, The EMBO journal.

[23]  D. Chitayat,et al.  Omphalocele in Miller-Dieker syndrome: expanding the phenotype. , 1997, American journal of medical genetics.

[24]  E. Steichen‐Gersdorf,et al.  Deletion mapping on chromosome 17p in medulloblastoma. , 1997, British Journal of Cancer.

[25]  Ahmed Mansouri,et al.  Follicular cells of the thyroid gland require Pax8 gene function , 1998, Nature Genetics.

[26]  J. Sambrook,et al.  Molecular Cloning: A Laboratory Manual , 2001 .

[27]  S. Baylin,et al.  HIC1 hypermethylation is a late event in hematopoietic neoplasms. , 1997, Cancer research.

[28]  D. Pilz,et al.  Syndromes with lissencephaly. , 1996, Journal of medical genetics.

[29]  B. Ljung,et al.  Loss of heterozygosity on the short arm of chromosome 17 is associated with high proliferative capacity and DNA aneuploidy in primary human breast cancer. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[30]  D. Ledbetter,et al.  Classical lissencephaly syndromes: does the face reflect the brain? , 1998, Journal of medical genetics.

[31]  D. Ledbetter,et al.  Subcortical band heterotopia in rare affected males can be caused by missense mutations in DCX (XLIS) or LIS1. , 1999, Human molecular genetics.

[32]  C. Wu,et al.  Repression of Drosophila pair-rule segmentation genes by ectopic expression of tramtrack. , 1993, Development.

[33]  S. Hirohashi,et al.  DNA hypermethylation at the D17S5 locus and reduced HIC‐1mRNA expression are associated with hepatocarcinogenesis , 1999, Hepatology.

[34]  D. Ledbetter,et al.  Genomic organization of the murine Miller-Dieker/lissencephaly region: conservation of linkage with the human region. , 1997, Genome research.

[35]  M. J. van de Vijver,et al.  Evidence for a gene on 17p13.3, distal to TP53, as a target for allele loss in breast tumors without p53 mutations. , 1994, Cancer research.

[36]  I. Sora,et al.  Opiate receptor knockout mice define mu receptor roles in endogenous nociceptive responses and morphine-induced analgesia. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

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

[38]  Y. Nakamura,et al.  Correlation of loss of alleles on the short arms of chromosomes 11 and 17 with metastasis of primary breast cancer to lymph nodes. , 1992, Cancer research.

[39]  Matthew H. Kaufman,et al.  The Atlas of Mouse Development , 1992 .

[40]  C. Montell,et al.  tramtrack is a transcriptional repressor required for cell fate determination in the Drosophila eye. , 1993, Genes & development.

[41]  S. Baylin,et al.  Regional DNA hypermethylation at D17S5 precedes 17p structural changes in the progression of renal tumors. , 1993, Cancer research.

[42]  N. Phillips,et al.  Allelic deletion on chromosome 17p13.3 in early ovarian cancer. , 1996, Cancer research.

[43]  K. Schughart,et al.  Isolation and embryonic expression of the novel mouse gene Hic1, the homologue of HIC1, a candidate gene for the Miller-Dieker syndrome. , 1999, Human molecular genetics.