User talk:PatrickTam

2011

Impact of WNT signaling on tissue lineage differentiation in the early mouse embryo

Dev Growth Differ. 2011 Jul 15. doi: 10.1111/j.1440-169X.2011.01292.x. [Epub ahead of print]

Tanaka SS, Kojima Y, Yamaguchi YL, Nishinakamura R, Tam PP. Source Department of Kidney Development, Institute of Molecular Embryology and Genetics (IMEG), Kumamoto University, Kumamoto, Japan Embryology Unit, Children's Medical Research Institute (CMRI), Westmead, NSW, Australia Global COE "Cell Fate Regulation Research and Education Unit", Kumamoto University, Kumamoto, Japan Sydney Medical School, The University of Sydney, Sydney, NSW, Australia.

Abstract

WNT signaling activity is involved in the regulation of many cellular functions, including proliferation, migration, cell fate specification, maintenance of pluripotency and induction of tumorigenicity. Here we summarize recent progress towards understanding the regulation of canonical WNT/β-catenin signaling activity through feedback regulatory loops involving the ligands, agonists and antagonists, the availability of intracellular pools of active β-catenin and the cross-regulation of the WNT activity by β-catenin independent pathway. We also review recent findings on the role of WNT/β-catenin signaling in tissue lineage differentiation during embryogenesis and the maintenance and self renewal of embryo-derived stem cells in vitro.

PMID 21762130

A novel transcript of cyclin-dependent kinase-like 5 (CDKL5) has an alternative C-terminus and is the predominant transcript in brain

Hum Genet. 2011 Jul 12. [Epub ahead of print]

Williamson SL, Giudici L, Kilstrup-Nielsen C, Gold W, Pelka GJ, Tam PP, Grimm A, Prodi D, Landsberger N, Christodoulou J. Source NSW Centre for Rett Syndrome Research, The Children's Hospital at Westmead, Sydney, NSW, 2145, Australia.

Abstract

The X-linked cyclin-dependent kinase-like 5 (CDKL5) gene is an important molecular determinant of early-onset intractable seizures with infantile spasms and Rett syndrome-like phenotype. The gene encodes a kinase that may influence components of molecular pathways associated with MeCP2. In humans there are two previously reported splice variants that differ in the 5' untranslated exons and produce the same 115 kDa protein. Furthermore, very recently, a novel transcript including a novel exon (16b) has been described. By aligning both the human and mouse CDKL5 proteins to the orthologs of other species, we identified a theoretical 107 kDa isoform with an alternative C-terminus that terminates in intron 18. In human brain and all other tissues investigated except the testis, this novel isoform is the major CDKL5 transcript. The detailed characterisation of this novel isoform of CDKL5 reveals functional and subcellular localisation attributes that overlap greatly, but not completely, with that of the previously studied human CDKL5 protein. Considering its predominant expression in the human and mouse brain, we believe that this novel isoform is likely to be of primary pathogenic importance in human diseases associated with CDKL5 deficiency, and suggest that screening of the related intronic sequence should be included in the molecular genetic analyses of patients with a suggestive clinical phenotype.

PMID 21748340

Sox17-dependent gene expression and early heart and gut development in Sox17-deficient mouse embryos

Int J Dev Biol. 2011;55(1):45-58.

Pfister S, Jones VJ, Power M, Truisi GL, Khoo PL, Steiner KA, Kanai-Azuma M, Kanai Y, Tam PP, Loebel DA. Source Embryology Unit, Children's Medical Research Institute, New South Wales, Australia.

Abstract

Sox17 is a transcription factor that is required for maintenance of the definitive endoderm in mouse embryos. By expression profiling of wild-type and mutant embryos and Sox17-overexpressing hepatoma cells, we identified genes with Sox17-dependent expression. Among the genes that were up-regulated in Sox17-null embryos and down-regulated by Sox17 expressing HepG2 cells is a set of genes that are expressed in the developing liver, suggesting that one function of Sox17 is the repression of liver gene expression, which is compatible with a role for Sox17 in maintaining the definitive endoderm in a progenitor state. Consistent with these findings, Sox17(-/-) cells display a diminished capacity to contribute to the definitive endoderm when transplanted into wild-type hosts. Analysis of gene ontology further revealed that many genes related to heart development were downregulated in Sox17-null embryos. This is associated with the defective development of the heart in the mutant embryos, which is accompanied by localised loss of Myocd-expressing cardiogenic progenitors and the malformation of the anterior intestinal portal.

PMID 21305474

Stringent requirement of a proper level of canonical WNT signalling activity for head formation in mouse embryo

Development. 2011 Feb;138(4):667-76. Epub 2011 Jan 12.

Fossat N, Jones V, Khoo PL, Bogani D, Hardy A, Steiner K, Mukhopadhyay M, Westphal H, Nolan PM, Arkell R, Tam PP. Source Embryology Unit, Children's Medical Research Institute, University of Sydney, 214 Hawkesbury Road, Westmead, Sydney, NSW 2145, Australia.

Abstract

In mouse embryos, loss of Dickkopf-1 (DKK1) activity is associated with an ectopic activation of WNT signalling responses in the precursors of the craniofacial structures and leads to a complete truncation of the head at early organogenesis. Here, we show that ENU-induced mutations of genes coding for two WNT canonical pathway factors, the co-receptor LRP6 and the transcriptional co-activator β-catenin, also elicit an ectopic signalling response and result in loss of the rostral tissues of the forebrain. Compound mutant embryos harbouring combinations of mutant alleles of Lrp6, Ctnnb1 and Dkk1 recapitulate the partial to complete head truncation phenotype of individual homozygous mutants. The demonstration of a synergistic interaction of Dkk1, Lrp6 and Ctnnb1 provides compelling evidence supporting the concepts that (1) stringent regulation of the level of canonical WNT signalling is necessary for head formation, (2) activity of the canonical pathway is sufficient to account for the phenotypic effects of mutations in three different components of the signal cascade and (3) rostral parts of the brain and the head are differentially more sensitive to canonical WNT signalling and their development is contingent on negative modulation of WNT signalling activity.

PMID 21228006