Search PubMed⌕ Search

Biomedical subjects

Patrick P L Tam

Publications and source records attributed to Patrick P L Tam.

At least 19 recordsLinked to original sources
PubMed2006

Sequential allocation and global pattern of movement of the definitive endoderm in the mouse embryo during gastrulation.

During mouse gastrulation, endoderm cells of the dorsal foregut are recruited ahead of the ventral foregut and move to the anterior region of the embryo via different routes. Precursors of the anterior-most part of the foregut and those of the mid- and hind-gut are allocated to the endoderm of the mid-streak-stage embryo, whereas the precursors of the rest of the foregut are recruited at later stages of gastrulation. Loss of Mixl1 function results in reduced recruitment of the definitive endoderm, and causes cells in the endoderm to remain stationary during gastrulation. The observation that the endoderm cells are inherently unable to move despite the expansion of the mesoderm in the Mixl1-null mutant suggests that the movement of the endoderm and the mesoderm is driven independently of one another.

Animals↗
PubMed2006

Genetic interaction of Gsc and Dkk1 in head morphogenesis of the mouse.

Mouse embryos lacking Gsc and Dkk1 function display severe deficiencies in craniofacial structures which are not found in either Dkk1 homozygous null or Gsc homozygous null mutant embryos. Loss of Gsc has a dosage-related effect on the severity of head truncation phenotype in Dkk1 heterozygous embryos. The synergistic effect of these mutations in enhancing head truncation provides direct evidence of a genetic interaction between Gsc and Dkk1, which display overlapping expression in the prechordal mesoderm. In the absence of Gsc activity, the expression of Dkk1, WNT genes and a transgenic reporter for WNT signalling are altered. Our results show that Gsc and Dkk1 functions are non-redundant in the anterior mesendoderm for normal anterior development and Gsc may influence Wnt signalling as a negative regulator.

Journal Article↗
PubMed2006

Building the mouse gastrula: signals, asymmetry and lineages.

The mouse embryo is built by assembling the progenitors of various tissue types into a body plan. Early postimplantation development involves the establishment of anatomical asymmetries and regionalized gene expression in the conceptus, the specification of tissue lineages, and the coordination of cell movement for correct positioning of the lineage progenitors before and at gastrulation. Recent findings reveal that Wnt and Tgfbeta signalling function is instrumental in delineating the anterior-posterior embryonic axis by defining the site of primitive streak formation and by directing the movement of the visceral endoderm. These signalling activities are also required for the specification of anterior and posterior fates of the epiblast cells and for the induction and navigation of the primordial germ cells.

Activins↗
PubMed2006

Stage-specific Importin13 activity influences meiosis of germ cells in the mouse.

Importin-mediated transport of cargoes is known to be a key mechanism for nucleo-cytoplasmic trafficking of molecules. Ipo13, which is a member of Importin-beta gene family, encodes two transcripts by utilizing different transcription start sites. In the mouse, the full-length transcript (L-Ipo13) is expressed in the primordial germ cells in the embryo and is later expressed predominantly at the pachytene phase of meiosis in both male and female germ cells. The shorter transcript (TS-Ipo13) is only expressed in the germ cells in the adult testis. Activity of L-Ipo13, but not TS-Ipo13, mediates the nuclear accumulation of ubiquitin-conjugating enzyme 9 (UBC9), a cargo of human IPO13. This finding is consistent with the progressive accumulation of UBC9 in the nucleus of the meiotic germ cells after the onset of L-Ipo13 expression. Following siRNA knockdown of IPO13 activity in the fetal ovary, fewer germ cells are found to progress to the late-pachytene stage of meiosis and nuclear accumulation of UBC9 is reduced. Our findings strongly implicate a stage-specific role of IPO13 in nuclear-cytoplasmic translocation of cargoes that accompanies meiotic differentiation of the mouse germ cells.

Amino Acid Sequence↗
PubMed2006

Expression analysis of the Epha1 receptor tyrosine kinase and its high-affinity ligands Efna1 and Efna3 during early mouse development.

Interaction of Eph receptor tyrosine kinases with their membrane bound ephrin ligands initiates bidirectional signaling events that regulate cell migratory and adhesive behavior. Whole-mount in situ hybridization revealed overlapping expression of the Epha1 receptor and its high-affinity ligands ephrin A1 (Efna1) and ephrin A3 (Efna3) in the primitive streak and the posterior paraxial mesoderm during early mouse development. These results show complex and dynamic expression for all three genes with expression domains that are successively complementary, overlapping, and divergent.

Animals↗
PubMed2006

Mecp2 deficiency is associated with learning and cognitive deficits and altered gene activity in the hippocampal region of mice.

Rett syndrome (RTT) is a debilitating neurological condition associated with mutations in the X-linked MECP2 gene, where apparently normal development is seen prior to the onset of cognitive and motor deterioration at 6-18 months of life. A targeted deletion of the methyl-CpG-binding domain (MBD) coding region and disruption of mRNA splicing was introduced in the mouse, resulting in a complete loss of Mecp2 transcripts and protein. Postnatal comparison of XO and XY mutant Mecp2 allele-containing null mice revealed similar effects on mouse growth and viability, suggesting that phenotypic manifestations are not modulated by the Y-chromosome. Further assessment of Mecp2-null XY mice highlighted cerebellar and hippocampal/amygdala-based learning deficits in addition to reduced motor dexterity and decreased anxiety levels. Brain tissues containing the hippocampal formation of XY Mecp2-null mice also displayed significant changes in genetic activity, which are related to the severity of the mutant phenotype.

Animals↗
PubMed2006

Expression of low density lipoprotein receptor-related protein 4 (Lrp4) gene in the mouse germ cells.

The low density lipoprotein receptor-related protein 4 gene (Lrp4) was identified by subtractive screening of cDNAs of the migratory primordial germ cells (PGCs) of E8.5-9.5 embryo and E3.5 blastocysts. Lrp4 is expressed in PGCs in the hindgut and the dorsal mesentery of E9.5 embryos, and in germ cells in the genital ridges of male and female E10.5-13.5 embryos. Lrp4 is also expressed in spermatogonia of the neonatal and adult testes and in the immature oocytes and follicular cells of the adult ovary. The absence of Lrp4 expression in the blastocyst, embryonic stem cells and embryonic germ cells suggests the Lrp4 is a molecular marker that distinguishes the germ cells from embryo-derived pluripotent stem cells.

Amino Acid Sequence↗
PubMed2006

Definitive endoderm of the mouse embryo: formation, cell fates, and morphogenetic function.

The endoderm is one of the primary germ layers but, in comparison to ectoderm and mesoderm, has received less attention. The definitive endoderm forms during gastrulation and replaces the extraembryonic visceral endoderm. It participates in the complex morphogenesis of the gut tube and contributes to the associated visceral organs. This review highlights the role of the definitive endoderm as a source of patterning cues for the morphogenesis of other germ-layer tissues, such as the anterior neurectoderm and the pharyngeal region, and also emphasizes the intricate patterning that the endoderm itself undergoes enabling the acquisition of regionalized cell fates.

Animals↗
PubMed2005

Reduced proportion of Purkinje cells expressing paternally derived mutant Mecp2308 allele in female mouse cerebellum is not due to a skewed primary pattern of X-chromosome inactivation.

Rett syndrome (RTT) is an X-linked disorder caused by mutations in the methyl CpG binding protein 2 (MECP2) gene. The pattern of X-chromosome inactivation (XCI) is thought to play a role in phenotypic severity. In the present study, patterns of XCI were assessed by lacZ staining of embryos and adult brains of mice heterozygous for a X-linked Hmgcr-nls-lacZ transgene on a mutant mouse model of RTT. We found that there was no difference between the lacZ staining patterns in the brain of wild-type and heterozygous mutant embryos at embryonic day 9.5 (E9.5) suggesting that Mecp2 has no effect on the primary pattern of XCI. At 20 weeks of age, there was no significant difference between XCI patterns in the Purkinje cells in the cerebellum of heterozygous mutant and wild-type mice when the mutant allele was inherited from the mother. However, when the mutant allele was paternally inherited, a significant difference was detected. Thus, parental origin of the mutation may have a bearing on phenotype through XCI patterns. An estimation of the Purkinje cell precursor number based on XCI mosaicism revealed that, when the mutation was paternally inherited, the precursor number was less than that in the wild-type mice. Therefore, it is likely that the number of precursor cells allocated to the Purkinje cell lineage is affected by a paternally inherited mutation in Mecp2. We also observed that the pattern of XCI in cultured fibroblasts was significantly correlated with patterns in the Purkinje cells in mutant animals but not in wild-type mice.

Animals↗
PubMed2005

IFITM/Mil/fragilis family proteins IFITM1 and IFITM3 play distinct roles in mouse primordial germ cell homing and repulsion.

The family of interferon-induced transmembrane protein (Ifitm/mil/fragilis) genes encodes cell surface proteins that may modulate cell adhesion and influence cell differentiation. Mouse Ifitm1 and -3, which are expressed in primordial germ cells (PGCs), are implicated to have roles in germ cell development, but the specific functions have been unclear. Our results show that Ifitm1 activity is required for PGC transit from the mesoderm into the endoderm, and that it appears to act via a repulsive mechanism, such that PGCs avoid Ifitm1-expressing tissues. In contrast, Ifitm3, which is expressed in migratory PGCs, is sufficient to confer autonomous PGC-like homing properties to somatic cells. These guidance activities are mediated by the N-terminal extracellular domain of the specific IFITM, which cannot be substituted by that of another family member. Complex homo- and/or heterotypic intercellular interactions among various IFITMs in PGCs and neighboring cells may underpin coordinated germ cell guidance in mice.

Animals↗
PubMed2005

Distinct expression profiles of Mecp2 transcripts with different lengths of 3'UTR in the brain and visceral organs during mouse development.

Four different transcripts of the Mecp2 gene can be distinguished by the length of the 3' untranslated region generated by usage of alternative polyadenylation sites. In situ hybridization analyses encompassing embryonic to 20-week postnatal age showed that transcripts are expressed in the central nervous system, with a progressive restriction during development culminating in localized strong expression in the cerebral cortex, olfactory bulb, hippocampal formation, and internal granule and Purkinje layer of the cerebellum. Real-time RT-PCR measurements of Mecp2 transcript levels showed variations with mouse age in two distinctive patterns that are unique to the central nervous system and the visceral organs, respectively. The 10-kb mRNA is the predominant form expressed in the brain in contrast to the shorter species expressed in the lung and liver. The developmental profile of Mecp2 mRNA highlights a potential tissue-specific function of the 3'UTR in the regulation of MeCP2 protein synthesis in response to the age-specific requirement of MeCP2 function during the life of the mouse.

3' Untranslated Regions↗
PubMed2005

A conserved noncoding intronic transcript at the mouse Dnm3 locus.

A 6-kb antisense transcript (Dnm3os) contained within an intron of the mouse Dnm3 gene has been identified in a screen for genes that may be regulated by the basic helix-loop-helix transcription factor Twist during mouse development. The antisense transcript is highly conserved between vertebrate species, but does not appear to encode a protein. We show that expression of the Dnm3 and Dnm3os transcripts overlaps during embryogenesis and in adult tissues, except that Dnm3 is most highly expressed in adult brain and testis and expressed at lower levels in embryos, whereas the antisense transcript is most strongly expressed in embryos and gravid uterus. Both Dnm3 and Dnm3os are downregulated in branchial arch tissue of Twist-null embryos. The conservation and restricted expression pattern of this noncoding transcript suggest that it may perform an important function during embryonic development and further suggest a connection between the regulation of Dnm3 and this novel intronic, antisense transcript.

Animals↗
PubMed2005

A gut feeling.

Explore the source record for details and available documents.

Animals↗
PubMed2004

Mutations of CDKL5 cause a severe neurodevelopmental disorder with infantile spasms and mental retardation.

Rett syndrome (RTT) is a severe neurodevelopmental disorder caused, in most classic cases, by mutations in the X-linked methyl-CpG-binding protein 2 gene (MECP2). A large degree of phenotypic variation has been observed in patients with RTT, both those with and without MECP2 mutations. We describe a family consisting of a proband with a phenotype that showed considerable overlap with that of RTT, her identical twin sister with autistic disorder and mild-to-moderate intellectual disability, and a brother with profound intellectual disability and seizures. No pathogenic MECP2 mutations were found in this family, and the Xq28 region that contains the MECP2 gene was not shared by the affected siblings. Three other candidate regions were identified by microsatellite mapping, including 10.3 Mb at Xp22.31-pter between Xpter and DXS1135, 19.7 Mb at Xp22.12-p22.11 between DXS1135 and DXS1214, and 16.4 Mb at Xq21.33 between DXS1196 and DXS1191. The ARX and CDKL5 genes, both of which are located within the Xp22 region, were sequenced in the affected family members, and a deletion of nucleotide 183 of the coding sequence (c.183delT) was identified in CDKL5 in the affected family members. In a screen of 44 RTT cases, a single splice-site mutation, IVS13-1G-->A, was identified in a girl with a severe phenotype overlapping RTT. In the mouse brain, Cdkl5 expression overlaps--but is not identical to--that of Mecp2, and its expression is unaffected by the loss of Mecp2. These findings confirm CDKL5 as another locus associated with epilepsy and X-linked mental retardation. These results also suggest that mutations in CDKL5 can lead to a clinical phenotype that overlaps RTT. However, it remains to be determined whether CDKL5 mutations are more prevalent in specific clinical subgroups of RTT or in other clinical presentations.

Amino Acid Sequence↗
PubMed2004

Regionalization of cell fates and cell movement in the endoderm of the mouse gastrula and the impact of loss of Lhx1(Lim1) function.

Investigation of the developmental fates of cells in the endodermal layer of the early bud stage mouse embryo revealed a regionalized pattern of distribution of the progenitor cells of the yolk sac endoderm and the embryonic gut. By tracing the site of origin of cells that are allocated to specific regions of the embryonic gut, it was found that by late gastrulation, the respective endodermal progenitors are already spatially organized in anticipation of the prospective mediolateral and anterior-posterior destinations. The fate-mapping data further showed that the endoderm in the embryonic compartment of the early bud stage gastrula still contains cells that will colonize the anterior and lateral parts of the extraembryonic yolk sac. In the Lhx1(Lim1)-null mutant embryo, the progenitors of the embryonic gut are confined to the posterior part of the endoderm. In particular, the prospective anterior endoderm was sequestered to a much smaller distal domain, suggesting that there may be fewer progenitor cells for the anterior gut that is poorly formed in the mutant embryo. The deficiency of gut endoderm is not caused by any restriction in endodermal potency of the mutant epiblast cells but more likely the inadequate allocation of the definitive endoderm. The inefficient movement of the anterior endoderm, and the abnormal differentiation highlighted by the lack of Sox17 and Foxa2 expression, may underpin the malformation of the head of Lhx1 mutant embryos.

Animals↗
PubMed2004

A specific requirement for PDGF-C in palate formation and PDGFR-alpha signaling.

PDGF-C is a member of the platelet-derived growth factor (PDGF) family, which signals through PDGF receptor (PDGFR) alphaalpha and alphabeta dimers. Here we show that Pdgfc(-/-) mice die in the perinatal period owing to feeding and respiratory difficulties associated with a complete cleft of the secondary palate. This phenotype was less severe than that of Pdgfra(-/-) embryos. Pdgfc(-/-) Pdgfa(-/-) embryos developed a cleft face, subepidermal blistering, deficiency of renal cortex mesenchyme, spina bifida and skeletal and vascular defects. Complete loss of function of both ligands, therefore, phenocopied the loss of PDGFR-alpha function, suggesting that both PDGF-A and PDGF-C signal through PDGFR-alpha to regulate the development of craniofacial structures, the neural tube and mesodermal organs. Our results also show that PDGF-C signaling is a new pathway in palatogenesis, different from, and independent of, those previously implicated.

Abnormalities, Multiple↗
PubMed2004

Regulation of murine telomere length by Rtel: an essential gene encoding a helicase-like protein.

Little is known about the genes that regulate telomere length diversity between mammalian species. A candidate gene locus was previously mapped to a region on distal mouse Chr 2q. Within this region, we identified a gene similar to the dog-1 DNA helicase-like gene in C. elegans. We cloned this Regulator of telomere length (Rtel) gene and inactivated its expression in mice. Rtel(-/-) mice died between days 10 and 11.5 of gestation with defects in the nervous system, heart, vasculature, and extraembryonic tissues. Rtel(-/-) embryonic stem cells showed telomere loss and displayed many chromosome breaks and fusions upon differentiation in vitro. Crosses of Rtel(+/-) mice with Mus spretus showed that Rtel from the Mus musculus parent is required for telomere elongation of M. spretus chromosomes in F1 cells. We conclude that Rtel is an essential gene that regulates telomere length and prevents genetic instability.

Abnormalities, Multiple↗