Impaired neurogenesis, learning and memory and low seizure threshold associated with loss of neural precursor cell survivin

Background

Survivin is a unique member of the inhibitor of apoptosis protein (IAP) family in that it exhibits antiapoptotic properties and also promotes the cell cycle and mediates mitosis as a chromosome passenger protein. Survivin is highly expressed in neural precursor cells in the brain, yet its function there has not been elucidated.

Results

To examine the role of neural precursor cell survivin, we first showed that survivin is normally expressed in periventricular neurogenic regions in the embryo, becoming restricted postnatally to proliferating and migrating NPCs in the key neurogenic sites, the subventricular zone (SVZ) and the subgranular zone (SGZ). We then used a conditional gene inactivation strategy to delete the survivin gene prenatally in those neurogenic regions. Lack of embryonic NPC survivin results in viable, fertile mice (Survivin ^Camcre ) with reduced numbers of SVZ NPCs, absent rostral migratory stream, and olfactory bulb hypoplasia. The phenotype can be partially rescued, as intracerebroventricular gene delivery of survivin during embryonic development increases olfactory bulb neurogenesis, detected postnatally. Survivin ^Camcre brains have fewer cortical inhibitory interneurons, contributing to enhanced sensitivity to seizures, and profound deficits in memory and learning.

Conclusions

The findings highlight the critical role that survivin plays during neural development, deficiencies of which dramatically impact on postnatal neural function.     

Coordination Chemistry of Nucleotides and Antivirally Active Acyclic Nucleoside Phosphonates,including Mechanistic Considerations

Considering that practically all reactions that involve nucleotides also involve metal ions, it is evident that the coordination chemistry of nucleotides and their derivatives is an essential corner stone of biological inorganic chemistry. Nucleotides are either directly or indirectly involved in all processes occurring in Nature. It is therefore no surprise that the constituents of nucleotides have been chemically altered—that is, at the nucleobase residue, the sugar moiety, and also at the phosphate group, often with the aim of discovering medically useful compounds. Among such derivatives are acyclic nucleoside phosphonates (ANPs), where the sugar moiety has been replaced by an aliphatic chain (often also containing an ether oxygen atom) and the phosphate group has been replaced by a phosphonate carrying a carbon–phosphorus bond to make the compounds less hydrolysis-sensitive. Several of these ANPs show antiviral activity, and some of them are nowadays used as drugs. The antiviral activity results from the incorporation of the ANPs into the growing nucleic acid chain—i.e., polymerases accept the ANPs as substrates, leading to chain termination because of the missing 3′-hydroxyl group. We have tried in this review to describe the coordination chemistry (mainly) of the adenine nucleotides AMP and ATP and whenever possible to compare it with that of the dianion of 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA²⁻ = adenine(N9)-CH₂-CH₂-O-CH₂-PO32) [or its diphosphate (PMEApp⁴⁻)] as a representative of the ANPs. Why is PMEApp⁴⁻ a better substrate for polymerases than ATP⁴⁻? There are three reasons: (i) PMEA²⁻ with its anti-like conformation (like AMP²⁻) fits well into the active site of the enzyme. (ii) The phosphonate group has an enhanced metal ion affinity because of its increased basicity. (iii) The ether oxygen forms a 5-membered chelate with the neighboring phosphonate and favors thus coordination at the P_α group. Research on ANPs containing a purine residue revealed that the kind and position of the substituent at C2 or C6 has a significant influence on the biological activity. For example, the shift of the (C6)NH₂ group in PMEA to the C2 position leads to 9-[2-(phosphonomethoxy)ethyl]-2-aminopurine (PME2AP), an isomer with only a moderate antiviral activity. Removal of (C6)NH₂ favors N7 coordination, e.g., of Cu²⁺, whereas the ether O atom binding of Cu²⁺ in PMEA facilitates N3 coordination via adjacent 5- and 7-membered chelates, giving rise to a Cu(PMEA)_cl/O/N3 isomer. If the metal ions (M²⁺) are M(α,β)-M(γ)-coordinated at a triphosphate chain, transphosphorylation occurs (kinases, etc.), whereas metal ion binding in a M(α)-M(β,γ)-type fashion is relevant for polymerases. It may be noted that with diphosphorylated PMEA, (PMEApp⁴⁻), the M(α)-M(β,γ) binding is favored because of the formation of the 5-membered chelate involving the ether O atom (see above). The self-association tendency of purines leads to the formation of dimeric [M₂(ATP)]₂(OH)⁻ stacks, which occur in low concentration and where one half of the molecule undergoes the dephosphorylation reaction and the other half stabilizes the structure—i.e., acts as the “enzyme” by bridging the two ATPs. In accord herewith, one may enhance the reaction rate by adding AMP²⁻ to the [Cu₂(ATP)]₂(OH)⁻ solution, as this leads to the formation of mixed stacked Cu₃(ATP)(AMP)(OH)⁻ species, in which AMP²⁻ takes over the structuring role, while the other “half” of the molecule undergoes dephosphorylation. It may be added that Cu₃(ATP)(PMEA) or better Cu₃(ATP)(PMEA)(OH)⁻ is even a more reactive species than Cu₃(ATP)(AMP)(OH)⁻. – The matrix-assisted self-association and its significance for cell organelles with high ATP concentrations is summarized and discussed, as is, e.g., the effect of tryptophanate (Trp⁻), which leads to the formation of intramolecular stacks in M(ATP)(Trp)³⁻ complexes (formation degree about 75%). Furthermore, it is well-known that in the active-site cavities of enzymes the dielectric constant, compared with bulk water, is reduced; therefore, we have summarized and discussed the effect of a change in solvent polarity on the stability and structure of binary and ternary complexes: Opposite effects on charged O sites and neutral N sites are observed, and this leads to interesting insights.     

Shape transformation of poly(butadiene)‐b‐poly(ethyleneoxide) plus DTAB compound micelles in aqueous solutions

The micellar shape of Poly(butadiene)‐b‐poly(ethyleneoxide) (PB‐PEO) plus Dodecyltrimethylammoniumbromide (DTAB) compound micelles was investigated by light scattering, small‐angle X‐ray scattering and small‐angle neutron scattering in dependence of the molar ratio between block copolymer and surfactant. The given block copolymer forms cylindrical micelles in binary aqueous solution, which transform to spherical aggregates upon the addition of a sufficiently high amount of DTAB. It is interesting to note that the micellar shape seems to be a bistable feature, in the sense that it depends not only on the molar ratio of BCP and DTAB but also in a predictable manner on the preparation procedure of the solution.