Region-specific expression of Dickkopf-like1 in the adult brain. Abbreviated title: Dkkl1 in the adult brain.

In the adult, the dickkopf family member Dickkopf-like1 (Dkkl1) has been described as a testicular protein involved in the regulation of spermatocyte apoptosis. However, microarray studies additionally suggested that Dkkl1 regulation is involved in various tumors including high grade gliomas. Since investigations of Dkkl1 in the adult central nervous system are lacking, we analyzed Dkkl1 expression in the adult mouse brain and found a region specific expression pattern with a profoundly high cortical expression. Analysis of transgenic mice in which the lacZ gene was inserted into the Dkkl1 locus further pointed to NeuN-positive neurons as the main source of Dkkl1 in the normal adult brain. In Dkkl1(-/-) mutant mice, gross brain morphology as well as hippocampal and cortical lamination appeared normal. Similarly, neuronal density in cortical layer V was not altered. Thus, Dkkl1 may not be essential for normal brain organization, but could exert import functions during pathological conditions such as tumorigenesis and cancer progression.

Role for Reelin in neurotransmitter release.

The extracellular matrix molecule Reelin is known to control neuronal migration during development. Recent evidence suggests that it also plays a role in the maturation of postsynaptic dendrites and spines as well as in synaptic plasticity. Here, we aimed to address the question whether Reelin plays a role in presynaptic structural organization and function. Quantitative electron microscopic analysis of the number of presynaptic boutons in the stratum radiatum of hippocampal region CA1 did not reveal differences between wild-type animals and Reelin-deficient reeler mutant mice. However, additional detailed analysis showed that the number of presynaptic vesicles was significantly increased in CA1 synapses of reeler mutants. To test the hypothesis that vesicle fusion is altered in reeler, we studied proteins known to control transmitter release. SNAP25, a protein of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex, was found to be significantly reduced in reeler mutants, whereas other SNARE complex proteins remained unaltered. Addition of recombinant Reelin to organotypic slice cultures of reeler hippocampi substantially rescued not only SNAP25 protein expression levels but also the number of vesicles per bouton area indicating a role for Reelin in presynaptic functions. Next, we analyzed paired-pulse facilitation, a presynaptic mechanism associated with transmitter release, and observed a significant decrease at CA1 synapses of reeler mutants when compared with wild-type animals. Together, these novel findings suggest a role for Reelin in modulating presynaptic release mechanisms.