Chronic granulomatous disease (CGD) is a recessive disorder characterized by a defective phagocyte respiratory burst oxidase, life-threatening pyogenic infections and inflammatory granulomas. Gene targeting was used to generate mice with a null allele of the gene involved in X-linked CGD, which encodes the 91 kD subunit of the oxidase cytochrome b. Affected hemizygous male mice lacked phagocyte superoxide production, manifested an increased susceptibility to infection with Staphylococcus aureus and Aspergillus fumigatus and had an altered inflammatory response in thioglycollate peritonitis. This animal model should aid in developing new treatments for CGD and in evaluating the role of phagocyte-derived oxidants in inflammation.

In mammals, the Rho family GTPase Rac2 is restricted in expression to hematopoietic cells, where it is coexpressed with Rac1. Rac2-deficient mice were created to define the physiological requirement for two near-identical Rac proteins in hematopoietic cells. rac2-/- neutrophils displayed significant defects in chemotaxis, in shear-dependent L-selectin-mediated capture on the endothelial substrate Glycam-1, and in both F-actin generation and p38 and, unexpectedly, p42/p44 MAP kinase activation induced by chemoattractants. Superoxide production by rac2-/- bone marrow neutrophils was significantly reduced compared to wild type, but it was normal in activated peritoneal exudate neutrophils. These defects were reflected in vivo by baseline neutrophilia, reduced inflammatory peritoneal exudate formation, and increased mortality when challenged with Aspergillus fumigatus. Rac2 is an essential regulator of multiple specialized neutrophil functions.

In 2007, the International Knockout Mouse Consortium (IKMC) made the ambitious promise to generate mutations in virtually every protein-coding gene of the mouse genome in a concerted worldwide action. Now, 5 years later, the IKMC members have developed high-throughput gene trapping and, in particular, gene-targeting pipelines and generated more than 17,400 mutant murine embryonic stem (ES) cell clones and more than 1,700 mutant mouse strains, most of them conditional. A common IKMC web portal (www.knockoutmouse.org) has been established, allowing easy access to this unparalleled biological resource. The IKMC materials considerably enhance functional gene annotation of the mammalian genome and will have a major impact on future biomedical research.

Adaptation to the environment is one of the fundamental regulatory processes in biology and is found among both simple and complex organisms. In a changing environment, simple organisms enhance species survival by high rates of spontaneous mutation achieved by several means: short maturation rates, rapid rates of reproduction, recombination through sexual reproduction, and large numbers of offspring. Then, by a process of natural selection, organisms that are adapted to their environment will survive and multiply. The process of natural selection also affects complex multicellular organisms and promotes adaptive changes. However, this simple strategy for survival becomes less effective in multicellular organisms as the ecological niche becomes more complex and the rates of maturation and fertility decrease. As a result, changes in the environment outpace the rate of genetic evolutionary change, which is limited by generation time. How do multicellular organisms produce adaptive change without genetic mutation?One solution to this problem is the development of complex physiological and behavioral systems coordinated by a CNS. The nervous system permits rapid adaptation to changing environmental conditions without genetic mutation (Kandel, 1984) by coordinating inputs from the internal and external environment via receptors and directing a complicated physiological response through various effector systems to maintain homeostasis. In many instances, homeostasis is maintained by reflexes and fixed action patterns in response to a stimulus. A problem arises when a stimulus or event in the environment does not determinately predict a condition or appropriate response to that condition.To cope with environmental complexity and ambiguity, an organism requires mechanisms that allow experience to affect relatively long-lasting changes in behavior. With a nervous system, the organism can accomplish this through a mechanism that has been called learning (Scott, 1965;Hilgard and Bower, 1975). According to the cellular connectionist hypothesis of Tanzi (1894) and Ramon y Cajal (1894), behavior modification is achieved by the strengthening of preexisting connections and by recombining potential combinations of dormant pathways between neural pathways that mediate innate response laid down during development or by the growth of new connections. Thus, recombination of connections between structural pathways increases the information storage capacity of the nervous system. So, how does the nervous system generate the diversity of cell types and connections and form long-term changes in synaptic connections as a result of experience (memory) with only 20,000 -30,000 genes in the vertebrate genome? Although somatic mutation in neuronal precursors through retrotransposon hopping has been proposed (Muotri et al., 2005) to generate diversity in the nervous system, as it does in the immune system, it is more likely that permanent changes in gene expression patterns are achieved through permanent changes in chromatin remodeling without...

The μ opioid receptor is thought to be the cellular target of opioid narcotics such as morphine and heroin, mediating their effects in both pain relief and euphoria. Its involvement is also implicated in a range of diverse biological processes. Using a mouse model in which the receptor gene was disrupted by targeted homologous recombination, we explored the involvement of this receptor in a number of physiological functions. Mice homozygous for the disrupted gene developed normally, but their motor function was altered. Drug-naive homozygotes displayed reduced locomotor activity, and morphine did not induce changes in locomotor activity observed in wild-type mice. Unexpectedly, lack of a functional receptor resulted in changes in both the host defense system and the reproductive system. We observed increased proliferation of granulocyte-macrophage, erythroid, and multipotential progenitor cells in both bone marrow and spleen, indicating a link between hematopoiesis and the opioid system, both of which are stress-responsive systems. Unexpected changes in sexual function in male homozygotes were also observed, as shown by reduced mating activity, a decrease in sperm count and motility, and smaller litter size. Taken together, these results suggest a novel role of the μ opioid receptor in hematopoiesis and reproductive physiology, in addition to its known involvement in pain relief.