Mouse embryonic brain development involves sequential differentiation of multipotent progenitors into neurons and glia cells. Using microarrays and large 2-DE, we investigated the mouse brain transcriptome and proteome of embryonic days 9.5, 11.5, and 13.5. During this developmental period, neural progenitor cells shift from proliferation to neuronal differentiation. As expected, we detected numerous expression changes between all time points investigated, but interestingly, the rate of alteration remained in a similar range within 2 days of development. Furthermore, up- and down-regulation of gene products was balanced at each time point which was also seen at embryonic days 16-18. We hypothesize that during embryonic development, the rate of gene expression alteration is rather constant due to limited cellular resources such as energy, space, and free water. A similar complexity in terms of expressed genes and proteins suggests that changes in relative concentrations rather than an increase in the number of gene products dominate cellular differentiation. In general, expression of metabolism and cell cycle related gene products was down-regulated when precursor cells switched from proliferation to neuronal differentiation (days 9.5-11.5), whereas neuron specific gene products were up-regulated. A detailed functional analysis revealed their implication in differentiation related processes such as rearrangement of the actin cytoskeleton as well as Notch- and Wnt-signaling pathways.
We have studied the process of tspy gene silencing in murine evolution. We have isolated functional tspy sequences from Apodemus agrarius, A. sylvaticus, A. flavicollis, and Mus platythrix (subgenus Pyromys) and nonfunctional tspy sequences from species of the subgenus Mus. We present two alternative models as to how tspy may have lost its function in the murine lineage.
Biological aging is often described by its phenotypic effect on individuals. Still, its causes are more likely found on the molecular level. Biological organisms can be considered as reliability-engineered, robust systems and applying reliability theory to their basic nonaging components, proteins, could provide insight into the aging mechanism. Reliability theory suggests that aging is an obligatory trade-off in a fault-tolerant system such as the cell which is constructed based on redundancy design. Aging is the inevitable redundancy loss of functional system components, that is proteins, over time. In our study, we investigated mouse brain development, adulthood, and aging from embryonic day 10 to 100 weeks. We determined redundancy loss of different protein categories with age using reliability theory. We observed a near-linear decrease of protein redundancy during aging. Aging may therefore be a phenotypic manifestation of redundancy loss caused by nonfunctional protein accumulation. This is supported by a loss of proteasome system components faster than dictated by reliability theory. This loss is highly detrimental to biological self-renewal and seems to be a key contributor to aging and therefore could represent a major target for therapies for aging and age-related diseases.
Brains of the mouse from three developmental stages, embryo day 16 (Ed16), postnatal stage one week (1W) and eight weeks (8W), were distributed to different laboratories for a collaborative proteome analysis (The Human Brain Proteome Project). As one of the laboratories involved in this project, we separated total protein extracts of the brains by large gel 2-DE. From the 2-DE protein patterns a section was evaluated for each of the three stages according to resolution, reproducibility and quantitative changes using an image analysis software. The evaluated pattern section was selected to allow comparisons of 2-DE patterns between different laboratories on the basis of optimum separation. Changes in protein expression were analysed within two phases of development: Stage Ed16 versus stage 1W and stage 1W versus stage 8W. Out of the 200 protein spots evaluated 5-6% showed quantitative changes in the range of > or = 30% between two stages. The relationship in the frequency of up- and down-regulated protein spots differed between the two investigated phases. Most of the protein spots which showed altered expression between two stages were identified by MS. High quality in protein separation and evaluation is demonstrated.
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