Genetic mapping of X-linked loci involved in skewing of X chromosome inactivation in the human. Naumova AK, Olien L, Bird LM, Smith M, Verner AE, Leppert M, Morgan K, Sapienza C: fur J Hum Genet 1998, 6:552-562. l Significance: First evidence for X-linked inheritance of X-chromosome inactivation. Findings: X-chromosome inactivation is not a random event. Skewed X-inactivation in human females can be measured trait showing strong sister-sister as a quantitative correlations, suggesting a heritable component. Using a sibpair study of 38 families with no genetic disease the authors showed that X-chromosome inactivation has “suggestive linkage” (p < 0.02) to 2 regions of the X-chromosome (Xql321 and Xq25-26).
of cancer-associated changes in human immortalized with telomerase. Morales CP, Holt
SE, Ouellette M, Kaur KJ, Yan Y, Wilson KS, White WE, Shay JW: Nat Genet 1999, 21 :115-l 18.
Telomerase expression in human somatic cells does not induce changes associated with a transformed phenotype. Jiang X-R, Jimenez G, Chang E, Frolkis M, Kusler B, Sage M, Beeche M, Bodnar AG, Wahl GM, Tisty TD, Chiu CP: Nat Genet 1999, 21 :l 1 l-1 14. l Significance: Although telomerase expression is a hallmark of cancer, these studies showed that hTERT, the catalytic centre of telomerase, doe not induce changes that allow tumour growth in viva. Findings: In both of these studies, constructs containing the catalytic component of human telomerase (hTERT) were used to transfect normal human fibroblasts. Transfected cell lines were assesed for cell-cycle control, oncogenic potential and cytogenetic features. It was shown that telomerase expression in normal somatic cells does not cause abnormal growth control, oncogenic transformation, or high levels of chromosomal aberrations/karyotype abnormalities. Morales et al. showed that co-expression of hTERT with viral oncoproteins - which cooperate with other “immortalizing mutations” to induce tumorigenic transformation - did not lead to evidence for tumorigenic changes. Jiang et al. performed an in viva tumorigenic assay and demonstrated that transfection of hTERT into nude mice did not induce tumour formation. Expression of hTERT does allow the development of primary human cells with extended or immortal lifespan which are a valuable tool for age-related diseases.
Loci on chromosomes increase susceptibility
2 (NIDDMI) and 15 interact to to diabetes in Mexican Americans.
Cox NJ, Frigge M, Nicolae DL, Concannon P, Hanis CL, Bell GI, Kong A: Nat Genet 1999, 21:213-215. l Significance: Description of a linkage analysis method that allows for the simultaneous consideration of multiple susceptibility loci. Findings: The authors show that evidence for linkage to one locus can be taken into account in assessing the evidence for linkage over the rest of the genome, by using the multi-point allele-sharing analysis in “GENEHUNTER-PLUS ~2.0’. This allows families to be weighted individually program according to structure, number of affecteds and/or linkage to a particular location, hence allowing analyses in the presence of positive interactions (such as epistasis) and heterogeneity. As
an example of the use of the approach, the paper details a study of diabetes in Mexican American Indians. Using data from a genome-wide scan that had previously identified a locus on chromosome 2, the authors looked for interactions with loci previously implicated in NlDDMl (from other studies) and with genes for MODY (maturity onset diabetes of the young). They detected an interaction on chromosome 15 (near CYPl9) which was replicated in a smaller, independent sample.
Pattern formation mechanisms
Selected by Mike Jones Section of Gene Function and Regulation, Laboratories, London, UK
Turning brain into blood: a hematopoietic fate adopted by adult neural stem cells in v&o. Bjornson CRR, Rietze RL, Reynolds BA, Magli MC, Vescovi AL: Science 1999, 283:534-537. l * Significance: Neural stem cells (NSCs) are demonstrated to possess a broader spectrum of differentiation potential than was previously suspected. Findings: NSCs isolated from embryonic and adult forebrains of ROSA26 mice (that constituitively express IacZ) were injected into sublethally irradiated hosts. The NSCs repopulate the bone marrow of the host and differentiate into a variety of blood cell types. A suggestion is made that cultured NSCs could provide a renewable source of cells to be used in the treatment of certain blood disorders.
Female development in mammals is regulated by Writ-4 signalling. Vainio S, Heikkila M, Kispert A, Chin N, McMahon AP: Nature 1999, 397:405-409. l * Significance: In this study, Wnt-4 is demonstrated to be essential
for normal female development. Targeted disruption of Writ-4 results in the development of masculinized female gonads, whereas Writ-4 null males are normal. Vhf-4 homozygous null embryos do not develop a Mullerian duct (in either females or males) and female germ cell survival is not supported.
Identification of a neural stem cell in the adult mammalian central nervous system. Johansson CB, Momma S, Clarke DL, Risling M, Lendahl U, Frisen J: Cell 1999, 96:25-34. Significance: The paper highlights the existence of neural stem cells in the ependymal layer of the ventricular system in the adult central nervous system (CNS). Findings: Single ependymal cells cultured in vitro are capable of generating neurons, astrocytes, and oligodendrocytes demonstrating that they are true stem cells. Neurons in the olfactory bulb are derived from ependymal cells. These stem cells are shown to increase their proliferation in response to injury within the CNS and to populate a transit amplifying population of progenitor cells in the subventricular zone. l
Visceral endoderm-restricted translation of Otxl mediates recovery of Otx2 requirements for specification of anterior neural plate and normal gastrulation. Acampora D, Avantaggiato
125:5091-5104. Significance: These
l findings lead to a hypothesis that differential post-transcriptional control between the visceral endoderm (VE) and epiblast may contribute to proper head development in the mouse embryo.
Findings: The Otu-2 coding
sequence was replaced by human Otx-7 sequences, and homozygous embryos of this genotype initiate normal head development and proper gastrulation. Transcripts encoding human Otx-1 are observed in the VE and the epiblast but the protein is only detected in the VE. Forebrain and midbrain identities are not maintained in these mice after midgestation stages.
Sonic hedgehog promotes somitic chondrogenesis by altering the cellular response to BMP signaling. Murtaugh LC, Chyung JH, Lassar AB: Genes Dev 1999,13:225-237. l Significance: The authors describe a two-step model where sequential signaling by Sonic Hedgehog (Shh) and bone morphogenetic proteins (BMPs) promotes cartilage differentiation. Findings: Presomitic mesoderm (PSM) from the chick is induced to form cartilage in response to Shh or lateral plate in response to BMP signaling. Transient early exposure to Shh changes the fate of PSM into sclerotome, which then responds to later BMP signaling resulting in chondrogenesis.
and gene regulation
Selected by Errc A Miska Wellcome/CRC Institute, Cambridge, UK
lin-35 and lin-53, two genes that antagonize a C. elegans ras pathway, encode proteins similar to Rb and its binding protein RbAp48. Lu X, Horvitz HR: Cell 1998, 95:981-991. l * Significance: This study presents the first in vivo evidence of retinoblastoma protein (Rb) and members of a deacetylase complex acting in the same pathway. Findings: In C. elegans, vulva1 induction is regulated by a ras signalling pathway. Here the authors describe two genes that antagonise ras action in vulva1 development, /in-35 and /in-53. /in-35 encodes a protein similar to the tumour suppressor Rb. /in-53 encodes a protein similar to Rbp48. Rbp48 was identified as an Rb-interacting protein and has recently been shown to be a member of a histone deacetylase complex that is thought to be recruited by Rb to repress transcription. Futhermore, the authors found C. elegans histone deacetylase hda-I, but not hda-2 or hda-3, to be gentically linked to vulva1 development. In addition, the authors demonstrated physical interaction between LIN-35, LIN-53 and HDA-1 in vitro. Finally, epistasis analysis suggested that /in-35 and /in-53 require a functional ras-signalling pathway.
The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus. Jacobs JJL, Kieboom K, Marino S, DePinho RA, van Lohuizen M: Nature 1999, 397:164-l 68. l 0 Significance: This is the first suggestion of an in vivo target for bmi-7, linking the Polycomb-group genes to cell-cycle control. (See also alert by Ridley, p 1 19.) Findings: Bmi-1 is a transcriptional repressor belonging to the mouse Polycomb group. It was initially identified as an protooncogene cooperating with c-myc in tumourigenesis. The mouse knock-out of bmi-I has been reported earlier, showing severe neurological defects and defective proliferation in lymphoid cells. In this study, the authors show that bmi-7 null mouse embryonic fibroblasts (MEFs) are defective in S-phase induction and undergo premature senescence. Both MEFs and lymphocytes lacking bmi-I overexpress pl6 and p79Arf, the two transcripts of ink4a. Overexpression of bmi-7 immortalised MEFs, downregulated the expression of ~76 and pi9Arf and
cooperated with H-ras in a colony formation assay. In addition, ink4&bmi-I-/double null mice had a partially rescued bmi? phenotype, suggesting that ink4a is a major target for bmi-I in vivo.
Turning brain into blood: a hematopoietic adult neural stem cells in ho. Bjornson Reynolds BA, 283:534-537.
CRR, Rietze RL, AL: Science 1999,
l Significance: Evidence for a differentiation potential of neural stem cells beyond the border of dermal origin. Findings: Stem cells, neural stem cells in particular, have been thought to be restricted to re-generate only specific cell-types, such as astrocytes, oligodendrocytes and neurons. In this study, mice were irradiated and implanted with genetically marked neural stem cells. Those were found to produce various cell types, also of a different dermal origin, namely a variety of blood cells. Myeloid, lymphoid and early hematopoietic cells were identified using specific cell-surface markers,
Selected by Reiko Toyama Laboratory of Molecular Genetics, National Institute of Chrld Health and Human Development, National Institute of Child Health, Bethesda, USA
A LIM-homeodomain code for motorneuron pathway selection. Thor S, Andersson SGE, Tomlinson A, Thomas JB: Nature
LIM homeodomain factors Lhx3 and Lhx4 assign subtype identities for motor neurons. Sharma K, Sheng HZ, Lettieri K, Li H, Karavanov 95:817-828.
A, Potter S, Westphal
H, Pfaff SL: Cell 1998,
l * Significance: It had previously been reported that different combinations of LIM-homeodomain proteins are expressed in different subsets of motor neurons in vertebrates but it is unclear what functional role these combinatorial differences may play. These particular studies suggest that different combinations of LIM homeodomain transcription factors determine motor neuron identity in Drosophila and mouse. They demonstrated that deletion or ectopic expression of one of these transcription factors is sufficient to alter motor neuron fate. Findings: Thor et al. isolated the Drosophila lim3 gene and found that it is co-expressed with islet, another LIM homeodomain protein, in a subset of motor neurons named ISNb whereas a second subset of motor neurons, ISNd, only expresses islet. Mutations in the lim3 gene cause ectopic innervation of ISNb motor neurons into the ISNd target. Moreover, mis-expressing lim3 in ISNd motor neurons switches ISNd projections to ISNb targets. In mouse, two lim3 related LIM-homeodomain genes, Lhx3 and Lhx4, are expressed in a subset of ventral motor neurons (v-MNs). In Lhx3/Lhx4 double knock-out but not single knock-out mice, the V-MN acquires properties of dorsal motor neurons (d-MNs). In addition, Lhx3 can specify V-MN identity when it is misexpressed in progenitors of d-MN cells.
Use of dsRNA-mediated genetic interference to demonstrate that frizzled and frizzled 2 act in the Wingless pathway. Kennerdell
RW: Cell 1998, 95:1017-l
frizzled and frizzled 2 play a partially redundant role in wingless signaling and have similar requirements to wingless in neurogenesis. Bhat KM: Cell 1998, 95:i 027-l 036.