Wee-Chuang Low

Publications (3)15.18 Total impact

• Article: The decoupling of Smoothened from Galphai proteins has little effect on Gli3 protein processing and Hedgehog-regulated chick neural tube patterning.

  Wee-Chuang Low, Chengbing Wang, Yong Pan, Xin-Yun Huang, James K Chen, Baolin Wang
  [show abstract] [hide abstract]
  ABSTRACT: The Hedgehog (Hh) signal is transmitted by two receptor molecules, Patched (Ptc) and Smoothened (Smo). Ptc suppresses Smo activity, while Hh binds Ptc and alleviates the suppression, which results in activation of Hh targets. Smo is a seven-transmembrane protein with a long carboxyl terminal tail. Vertebrate Smo has been previously shown to be coupled to Galpha(i) proteins, but the biological significance of the coupling in Hh signal transduction is not clear. Here we show that although inhibition of Galpha(i) protein activity appears to significantly reduce Hh pathway activity in Ptc(-/-) mouse embryonic fibroblasts and the NIH3T3-based Shh-light cells, it fails to derepress Shh- or a Smo-agonist-induced inhibition of Gli3 protein processing, a known in vivo indicator of Hh signaling activity. The inhibition of Galpha(i) protein activity also cannot block the Sonic Hedgehog (Shh)-dependent specification of neural progenitor cells in the neural tube. Consistent with these results, overexpression of a constitutively active Galpha(i) protein, Galpha(i2)QL, cannot ectopically specify the neural cell types in the spinal cord, whereas an active Smo, SmoM2, can. Thus, our results indicate that the Smo-induced Galpha(i) activity plays an insignificant role in the regulation of Gli3 processing and Shh-regulated neural tube patterning.
  Developmental Biology 07/2008; 321(1):188-96. · 4.07 Impact Factor
• Article: CADASIL-causing mutations do not alter Notch3 receptor processing and activation.

  Wee-Chuang Low, Yo Santa, Keikichi Takahashi, Takeshi Tabira, Raj N Kalaria
  [show abstract] [hide abstract]
  ABSTRACT: CADASIL is associated with mutations in the Notch3 gene but the causal mechanisms of the disorder remain unclear. We studied effects of widely established mutations on Notch3 receptor processing and ligand-mediated activation in stable lines of HEK293 and SH-SY5Y cells expressing either human wild-type or mutant Notch3 receptor. None of the four mutations (R90C, R133C, C185R and R449C) affected quantities of the full-length, amino-terminal or carboxyl-terminal fragments and did not impair intracellular trafficking in both cell types. The Jagged 1, Jagged 2 and Delta ligand-mediated S2 site cleavage and signal transduction were also observed to be similar in both wild-type and mutants, which exhibited similar rates of degradation of full-length, amino-terminal and carboxyl-terminal fragments. Our results suggest that the arteriopathy in CADASIL is caused by other mechanisms not necessarily involving Notch3 processing and activation.
  Neuroreport 08/2006; 17(10):945-9. · 1.66 Impact Factor
• Article: Novel presenilin 1 mutation with profound neurofibrillary pathology in an indigenous Southern African family with early-onset Alzheimer's disease.

  Jeannine M Heckmann, Wee-Chuang Low, Cora de Villiers, Stuart Rutherfoord, Alvera Vorster, Harpal Rao, Christopher M Morris, Raj S Ramesar, Raj N Kalaria
  [show abstract] [hide abstract]
  ABSTRACT: Genetically determined Alzheimer's disease (AD) is virtually unknown in Africa. We report clinicopathological findings and a presenilin 1 (PS1) mutation associated with early-onset AD in a large Xhosa family from Southern Africa. Twelve individuals spanning four generations were affected, four of whom underwent clinical and psychometric evaluation. Their phenotype was characterized by memory impairment beginning in the early part of the fifth decade, with progressive dementing illness lasting 6-7 years that did not appear to be modified by the presence of an apolipoprotein E (APOE)-epsilon 4 allele. Initial linkage-based analysis using known DNA markers suggested allele cosegregation with a locus on chromosome 14. Direct sequencing of the PS1 gene disclosed a novel I143M (ATT to ATG at nucleotide 677) mutation that lies in a cluster in the second transmembrane domain of the protein. Examination of the proband's brain at autopsy revealed severe AD pathology characterized by neuronal loss, abundant beta amyloid (A beta) neuritic plaques (A beta 42) and neurofibrillary degeneration extending into the brainstem. The phenotype of the I143M mutation was clearly associated with a high degree of neurofibrillary change compared with early-onset sporadic AD cases. Although sporadic cases of AD do exist in African populations, our study confirms the existence of early-onset familial AD among indigenous Southern Africans.
  Brain 01/2004; 127(Pt 1):133-42. · 9.46 Impact Factor