No abstract

We show that DCC and netrin-1 are ubiquitously expressed in the human foetal brain; however, both exhibit a distinct spatio-temporal expression pattern. Together with the data from animal experiments, our findings might indicate also an important role for DCC and netrin-1 in human foetal CNS development.

The erythropoietin receptor (EPO-R) is mainly known as a regulator of erythropoiesis. However, recent studies revealed that the EPO-R is not exclusively expressed in haematopoietic tissues but also in various cancer cell types and normal tissue such as the central nervous system (CNS). EPO-R is up-regulated under hypoxia and is able to counteract the deleterious effects of hypoxia on tumour growth, metastasis and treatment resistance. Therefore, the EPO-EPO-R signalling pathway is considered as a possible target for tumour treatment. Here, we investigated brain tumour samples obtained from patients between 1993 and 2003 to study EPO-R expression in vivo. Tissue samples included 194 gliomas of different WHO grades, additionally 25 infiltration zone samples and 31 relapses of WHO grade IV glioblastomas as well as 23 normal CNS tissue specimens to address the in vivo situation. Immunohistochemistry of the tissue microarray samples revealed significantly higher levels of EPO-R expression in neoplastic glial cells compared with glial cells derived from normal brain. EPO-R expression showed a highly significant decrease from low- to high-grade gliomas. Age-stratified Kaplan-Meier analysis revealed longer survival for patients exhibiting high EPO-R status in high-grade gliomas. Our results show a grade-dependent EPO-R down-regulation and might contribute to the understanding of high-grade glioma resistance to radio- and chemotherapy as both were shown to be improved by a well functioning EPO-EPO-R pathway in previous studies. Further studies are needed to investigate to what extent the decreased mortality in age-stratified patient groups with high EPO-R levels reflects a direct beneficial role of EPO-R expression.

The Sonic Hedgehog (SHH) pathway plays a central role in the developing mammalian CNS. In our study, we aimed to investigate the spatiotemporal SHH pathway expression pattern in human fetal brains. We analyzed 22 normal fetal brains for Shh, Patched, Smoothened, and Gli1-3 expression by immunohistochemistry. In the telencephalon, strongest expression of Shh, Smoothened, and Gli2 was found in the cortical plate (CP) and ventricular zone. Patched was strongly upregulated in the ventricular zone and Gli1 in the CP. In the cerebellum, SHH pathway members were strongly expressed in the external granular layer (EGL). SHH pathway members significantly decreased over time in the ventricular and subventricular zone and in the cerebellar EGL, while increasing levels were found in more superficial telencephalic layers. Our findings show that SHH pathway members are strongly expressed in areas important for proliferation and differentiation and indicate a temporal expression gradient in telencephalic and cerebellar layers probably due to decreased proliferation of progenitor cells and increased differentiation. Our data about the spatiotemporal expression of SHH pathway members in the developing human brain serves as a base for the understanding of both normal and pathological CNS development.