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despite a 50-fold excess of molecules of vWf in plasma
compared with FVIII. In type 2 vWd, the level of FVIII
is usually normal except in a particular variant (type
2N) which presents a defective binding of vWf to FVIII
due to point mutations in the vWf gene.
As  a  result  of  the  decrease  of  FVIII  in  vWd,  the
activated partial thromboplastin time may be abnormal.
This assay detects abnormalities in the amplification of
the coagulation cascade, and if the FVIII level is sub-
stantially decreased, the clotting time measured by that
test  is  prolonged.  In  contrast,  assays  such  as  the
prothrombin time, which detects abnormalities in the
extrinsic coagulation pathway, is not affected.



Porcine vWd

A bleeding disorder was described in swine in 1941 by

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Abstract

Activation of the KIT receptor tyrosine kinase contributes to the pathogenesis of several human diseases, but the mechanisms regulating KIT signaling have not been fully characterized. Here, we show that stem cell factor (SCF), the ligand for KIT, in...



Introduction

KIT, the stem cell factor (SCF) receptor, is a receptor protein tyrosine kinase (RTK) that is primarily expressed on mast cells, hematopoietic stem cells, germ cells, melanocytes, and the interstitial cells of Cajal. 1, 2 Studies in white-spotting an...



Ubiquitination and subsequent degradation of proteins has been implicated as a key mechanism regulating duration and intensity of many intracellular signals, and it has been suggested that activated KIT is degraded through the polyubiquitination-depe...



Cbl family members are newly established as components of the ubiquitin ligation machinery involved in the degradation of phosphorylated proteins. 8 In vitro assays have shown that Cbl proteins can function as E3 ubiquitin (Ub) ligases, and Cbl prote...

t/data/demos/15328020.cp1252  view on Meta::CPAN

 c Beth Israel Deaconess Medical Center, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA



 d Department of Pharmacology, University of North Carolina, Neuroscience Research Building, Chapel Hill, NC 27599-7250, USA

   Received 14 April 2004; revised 18 June 2004; accepted 22 June 2004. Available online 27 July 2004.    Abstract 

 Neurogenin ( Ngn ) 1 and Ngn2 encode basic-helix-loop-helix transcription factors expressed in the developing neocortex. Like other proneural genes, Ngns participate in the specification of neural fates and neuronal identities, but downstream effect...

   

 Keywords: neocortex development; Neurogenin ; downstream effectors; thalamocortical; subplate; neuronal specification; axonal targeting

   

 Abbreviations: CP, cortical plate; dig, digoxygenin; E, embryonic day; gz, germinal zone; IZ, intermediate zone; Ngn, Neurogenin; P, postnatal day; pp, preplate; sp, subplate; SVZ, subventricular zone; TCA, thalamocortical afferent; VZ, ventricular ...

    Article Outline Introduction Materials and methods Maintenance and genotyping of Ngn2 lacZ and Ngn1 mutant mice beta-galactosidase detection and cell sorting RNA extraction, cDNA synthesis, and subtraction Identification and isolation of full-len...

The neocortex is subdivided into more than 40 tangential areas and six radial layers, each characterized by unique neuronal morphologies, axonal projections, molecular identities, and functions ( Job and Tan, 2003 ). The striking degree of neuronal d...



 Ngn1 and Ngn2, which encode basic-helix-loop-helix (bHLH) transcription factors with proneural activity ( Fode et al., 1998, Fode et al., 2000 and Ma et al., 1998 ), contribute to the specification of a neuronal versus glial identity in cortical pro...



The changes in cell-fate exhibited following ectopic expression of Mash1 in Ngn1/2 expression domains are analogous to those obtained when the Drosophila proneural achaete-scute genes are ectopically expressed in precursors that normally express aton...



In order to understand better the genetic program(s) executed by the proneural gene Ngn2 in the neocortex, we performed a subtractive hybridization screen between wild-type and Ngn2 mutant telencephalons. We identified 46 genes expressed in the embry...

 Materials and methods Maintenance and genotyping of Ngn2 lacZ and Ngn1 mutant mice 

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 RNA in situ hybridization 

RNA in situ hybridization was carried out on 10 mum cryostat sections as previously described ( Cau et al., 1997 ). Digoxygenin (dig)-labeled RNA probes were generated using T3, T7, or SP6 RNA polymerases and a dig-RNA-labeling mix (Roche). In additi...

 Immunohistochemistry, histology, and birthdating 

For histology, P0 brains were fixed in Bouin's fixative for 3 days, dehydrated in an ethanol–xylene series, embedded in paraffin, and 7 mum sections were cut and stained with hematoxylin–eosin as described previously ( Rhinn et al., 1998 ). For birth...

 Results Construction of a subtracted cDNA library enriched for neocortical genes dependent on Ngn2 function 

Early born preplate and deep-layer cortical plate neurons are misspecified in Ngn2 mutants, acquiring a GABAergic rather than glutamatergic identity ( Fode et al., 2000 and Schuurmans et al., 2004 ). To identify downstream components of the Ngn1/2 -d...

 Full-size image (163K) 

Fig. 1.Experimental design for subtracting expressed genes in Ngn2 lacZ +/- (”wild-type”) and Ngn2 lacZ -/- (”mutant”) cortical cells. (A) Frontal section of E13.5 telencephalon hybridized with a probe for Ngn2. (B) X-gal staining of frontal sections...

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For each embryo, betagal (+) cortical cells were separated from betagal (-) cells by flow cytometry (FACS), yielding 8000–10,000 cells. RNA was extracted from betagal (+) cells and cDNA was synthesized and amplified by PCR. Two rounds of subtraction ...

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We examined the distribution of TCAs first by immunostaining with an anti-L1 antibody ( Figs. 6 A–F), which revealed an aberrant organization and fasciculation of thalamic axonal tracts that disrupted the cortical germinal zone in E18.5 Ngn2 mutants....

 Full-size image (181K) 

Fig. 6.Thalamocortical and corticofugal projections are perturbed in Ngn2 and Ngn1;Ngn2 mutants. (A–F) L1 immunostaining of E18.5 wild-type (A–C) and Ngn2 mutant (D–F) sagittal sections through the cortex revealed aberrant axonal bundles (arrowheads)...

 View Within Article Discussion 

The primary objective of this study was to gain new insights into the transcriptional program(s) executed downstream of the proneural transcription factor Ngn2. In this regard, our subtractive screen was successful; leading to the identification of t...

 Identification of differentiation cascades activated downstream of Ngn2 

Before this screen, we knew that Ngn1 and Ngn2 activities were absolutely required to induce a dorsal, glutamatergic-specific differentiation program in early born cortical neurons, but known components of the downstream pathway included only HLH (i....



Although genomic analyses for proneural-regulated genes have not been conducted in most neural lineages, analyses of expression profiles of candidate target genes in proneural mutants have led to the identification of several downstream genes that ty...



A second broad category of proneural-regulated genes includes markers of a mature neuronal phenotype, such as NCAM, neurofilament, and the ELAVL4 homologs ELAV and HuC/HuD ( Ferreiro et al., 1994, Park et al., 2003 and zur Lage et al., 2003 ). Here w...



Proneural transcription factors are known to be required to activate genes involved in cell–cell communication, such as rhomboid, scabrous, delta, c-RET, and the neuropeptide receptor NKD ( Heitzler et al., 1996, Lo et al., 1998, Okabe and Okano, 199...

 Full-size image (39K) 

Fig. 7.Model depicting Ngn2 -dependent genetic cascades in the cortex. Pax6 directly regulates Ngn2 (solid arrow; Scardigli et al., 2003 ), but whether Ngn2 directly regulates any of the targets identified in our screen remains to be determined (brok...

 View Within Article 

In summary, the wide range of Ngn1 - and Ngn2 -regulated genes uncovered in our screen suggests that these proneural transcription factors regulate a multitude of cellular processes ( Fig. 7 ). This is highly analogous to myogenic bHLH transcription ...

 Identification of a new biological function for Ngn2 in guiding TCAs trajectories in the neocortex 

We have shown here that subplate neurons, which normally provide attractive cues for TCAs, are disorganized in Ngn2 and Ngn1;Ngn2 mutants. Moreover, Ngn2 mutant subplate neurons are misspecified and fail to express genes like Mef2c, protocadherin 9, ...



The abnormal differentiation of the subplate layer in Ngn2 and Ngn1;Ngn2 mutants initially prompted us to examine the projection patterns of TCAs in mutant cortices given the known role of the subplate in guiding these axons. Indeed, we found that TC...

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 Burns and Vetter, 2002 C.J. Burns and M.L. Vetter, Xath5 regulates neurogenesis in the Xenopus olfactory placode, Dev. Dyn. 225 (2002), pp. 536–543. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (7) 



 Cabrera and Alonso, 1991 C.V. Cabrera and M.C. Alonso, Transcriptional activation by heterodimers of the achaete-scute and daughterless gene products of Drosophila, EMBO J. 10 (1991), pp. 2965–2973. 



 Cau et al., 1997 E. Cau, G. Gradwohl, C. Fode and F. Guillemot, Mash1 activates a cascade of bHLH regulators in olfactory neuron progenitors, Development 124 (1997), pp. 1611–1621. View Record in Scopus | Cited By in Scopus (191) 



 Cau et al., 2002 E. Cau, S. Casarosa and S. Guillemot, Mash1 and Ngn1 control distinct steps of determination and differentiation in the olfactory sensory neuron lineage, Development 129 (2002), pp. 1871–1880. View Record in Scopus | Cited By in Sco...



 Chen et al., 1997 H. Chen, A. Chedotal, Z. He, C.S. Goodman and M. Tessier-Lavigne, Neuropilin-2, a novel member of the neuropilin family, is a high affinity receptor for the semaphorins Sema E and Sema IV but not Sema III, Neuron 19 (1997), pp. 547...