Knock-out mice for

Knock-out mice, for a transcription factor T-bet (required for Thl-cell synthesis), make fewer Thl and more Th2 cells, and suffer the lung changes typical of human asthma, even though they are not exposed to any particnlar allergen. 

Increasing evidence suggests that members of the Bcl-2 family may act not only at the mitochondrial levels but also at the ER level. There is work that suggests that Bak and Bax are involved in controlling Ca " " homeostasis in the ER because double knock-out mice for Bax and Bak exhibit impaired Ca " efflux from the ER and uptake by the mitochondria this is correlated with low levels of apoptotic cell death (Nutt et al., 2002b, a). The relevance of these data to human neurodegenerative disorders is not yet clear because so far only caspase-12 has been reported to become activated after ER stress-induced apoptosis. There is evidence showing that both Bax... 

Interestingly, single or double knock-out mice for the Hasl or the Has3 genes are viable and fertile, and have no apparent phenotype, while the Has2 knock-out mouse is an embryonic lethal. Among the many abnormalities is the need for HAS2 for normal cardiac development, particularly the cardiac cushion [98]. 

HT is metabolised primarily by MAO to 5-hydroxyindoleacetic acid (5-HIAA) (Fig. 9.4). In vitro, 5-HT is the preferred substrate for the MAOa, rather than the MAOb isoenzyme (see Chapter 8) and this appears to be the case in vivo since MAOa, but not MAOb, knock-out mice have increased concentrations of 5-HT in the brain. Obviously, because of its indole nucleus, 5-HT is not a substrate for the enzyme COMT which metabolises the catechol derivatives, dopamine and noradrenaline. However, other metabolic products of 5-HT are theoretically possible and one, 5-hydroxytryptophol,... 

Nitric oxide has also been implicated in PD. Thus animals with MPTP-induced Parkinsonism not only show extensive gliosis in the substantia nigra (like humans) in which the glial cells produce NO, but Liberatore and colleagues have found that in iNOS (inducible nitric oxide synthase) knock-out mice the toxicity of MPTP is halved. Since NO releases iron from ferritin and produces toxic peroxinitrate in the presence of superoxide radicals it could accelerate, even if it does not initiate, dopaminergic cell death (see Hirsch and Hunot 2000 for further details). 

There are few specific drugs for D3 receptors but D3 knock-out mice show no behavioural defects. Thus the significance of any DA receptor other than the D2 still remains to be established (see Seeman and Van Tol 1994 Sokoloff and Schwartz 1995 Strange 1994). 

The increased dopamine hypothesis is supported by findings of gene induction in the target areas and the indications that individual differences in dopamine receptors and transporters may underlie impulsive and addictive behaviour in humans. Studies in knock-out mice have, however, provided evidence for complex roles of 5-HT in these processes. 

Parmentier, R., Ohtsu, H., Djebbara-Hannas, Z., Valatx, J. L., Watanabe, T. and Lin, J. S. Anatomical, physiological, and pharmacological characteristics of histidine decarboxylase knock-out mice evidence for the role of brain histamine in behavioral and sleep-wake control. /. Neurosci. 22 7695-7711,2002. 

AP has a very effective binding domain for copper in its N-terminal domain and can bind copper in nanomolar amounts (Figure 18.15). It is unclear whether APP or AP when associated with copper, are in fact neuronal metallochaperones. Knock out and knock in mice for APP show that in the former, cerebral cortex copper levels are increased, whereas in the latter reduced copper levels were found. Copper was also influential in APP processing in the cell copper will reduce levels of Ap and cause an increase in the secretion of the APP ectodomain. 

The role of the steroid hormone receptors has extensively been defined with the help of natural and synthetic agonists and antagonists and with characterisation of transgenic and knock-out mice. In experimental studies, both approaches have been useful tools for validating that a physiological process is indeed mediated by the steroid hormone receptor imder investigation. 

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