Background: Long considered to be the building block of life, it is now apparent that protein is only one of many functional products generated by the eukaryotic genome. Indeed, more of the human genome is transcribed into noncoding sequence than into protein-coding sequence. Nevertheless, whilst we have developed a deep understanding of the relationships between evolutionary constraint and function for protein-coding sequence, little is known about these relationships for non-coding transcribed sequence. This dearth of information is partially attributable to a lack of established non-protein-coding RNA (ncRNA) orthologs among birds and mammals within sequence and expression databases.
The major lineages of mammals (Eutheria, Metatheria, and Monotremata) diverged more than 100 million years ago and have undergone independent changes in the neocortex. We found that adult South American gray short-tailed opossum (Monodelphis domestica) and tammar wallaby (Macropus eugenii) possess a significantly lower number of cerebral cortical neurons compared with the mouse (Mus musculus). To determine whether the difference is reflected in the development of the cortical germinal zones, the location of progenitor cell divisions was examined in opossum, tammar wallaby, and rat. The basic pattern of the cell divisions was conserved, but the emergence of a distinctive band of dividing cells in the subventricular zone (SVZ) occurred relatively later in the opossum (postnatal day [P14]) and the tammar wallaby (P40) than in rodents. The planes of cell divisions in the ventricular zone (VZ) were similar in all species, with comparable mRNA expression patterns of Brn2, Cux2, NeuroD6, Tbr2, and Pax6 in opossum (P12 and P20) and mouse (embryonic day 15 and P0). In conclusion, the marsupial neurodevelopmental program utilizes an organized SVZ, as indicated by the presence of intermediate (or basal) progenitor cell divisions and gene expression patterns, suggesting that the SVZ emerged prior to the Eutherian-Metatherian split.
Although the specific mechanism of neuronal damage in human immunodeficiency virus (HIV) -associated dementia is not known, a prominent role for NMDA receptor (NMDAR)-induced excitotoxicity has been demonstrated in neurons exposed to HIV-infected/activated macrophages. We hypothesized NMDAR-mediated activation of the calcium-dependent protease, calpain, would contribute to cell death by induction of cyclin-dependent kinase 5 (CDK5) activity. Using an in vitro model of HIV neurotoxicity, in which primary rat cortical cultures are exposed to supernatants from primary human HIV-infected macrophages, we have observed increased calpain-dependent cleavage of the CDK5 regulatory subunit, p35, to the constitutively active isoform, p25. Formation of p25 is dependent upon NMDAR activation and calpain activity and is coincident with increased CDK5 activity in this model. Further, inhibition of CDK5 by roscovitine provided neuroprotection in our in vitro model. Consistent with our observations in vitro, we have observed a significant increase in calpain activity and p25 levels in midfrontal cortex of patients infected with HIV, particularly those with HIV-associated cognitive impairment. Taken together, our data suggest calpain activation of CDK5, a pathway activated in HIVinfected individuals, can mediate neuronal damage and death in a model of HIV-induced neurotoxicity. Keywords: calpain, cyclin-dependent kinase 5, cell cycle, dementia, encephalitis, neurodegeneration, NMDA receptor. Before the widespread use of highly active antiretroviral therapy (HAART), approximately 20% of patients infected with human immunodeficiency virus (HIV) developed HIVassociated dementia (HAD) (Kaul et al. 2001;Garden 2002;Gonzalez-Scarano and Martin-Garcia 2005). In the post-HAART era, the incidence of HAD has declined to approximately 8%; however, the prevalence has increased. In addition, an increasing number (40%) of HIV-infected patients on HAART are developing a constellation of less severe neurologic symptoms referred to as minor cognitive motor disorder (MCMD) (Janssen et al. 1989;Sacktor et al. 2002;McArthur et al. 2003). Pathologic studies of the brains of patients with HAD suggest an inflammatory mechanism in the progression of this disease, as evidenced by astrogliosis, microgliosis, and perivascular macrophage infiltration (Kaul et al. 2001;Garden 2002;Ghorpade et al. 2003). Although neuronal, dendritic, and synaptic loss are features of HAD, there is little evidence of direct HIV infection of neurons (Shi et al. 1996;Corasaniti et al. 2001). Instead, neuronal dys- Abbreviations used: CDK5, cyclin-dependent kinase 5; DIV, days in vitro; DTT, dithiothreitol; ERK1/2, extracellular signal-regulated kinase 1 and 2; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HAART, highly active antiretroviral therapy; HAD, HIV-associated dementia; HIV MDM, HIV-infected, monocyte-derived macrophage; HIV, human immunodeficiency virus; HIVE, human immunodeficiency virus encephalitis; LR, linear range; MAP2, microtubule-associated protein 2...
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