Netrin1 is required for neural and glial precursor migrations into the olfactory bulb

Abstract

Netrin1 (NTN1) deficiency in mouse brain causes defects in axon guidance and cell migration during embryonic development. Here we show that NTN1 is required for olfactory bulb (OB) development at late embryogenesis and at early postnatal stages to facilitate the accumulation of proper numbers of granular and glomerular neuron subtypes and oligodendrocytes into the OB. In addition to the analysis of Ntn1-/- mice we made tissue and neurosphere cultures to clarify the role of NTN1 in the anterior forebrain. We propose that a subset of neural progenitors/precursors requires NTN1 to efficiently enter the rostral migratory stream to migrate into the OB. The analysis of postnatal Ntn1-/- OBs revealed a reduction of specific types of interneurons which have been shown to originate from particular subregions of the lateral ventricle walls. Based on Ntn1 expression in ventral parts of the ventricle walls, we observed a decrease in the mainly ventrally derived type II interneurons that express calcium-binding proteins calretinin and calbindin. Instead, no change in the numbers of dorsally derived tyrosine hydroxylase expressing interneurons was detected. In addition to the specific reduction of type II interneurons, our results indicate that NTN1 is required for oligodendroglial migration into the OB. Furthermore, we characterised the Ntn1 expressing subpopulation of neurosphere-forming cells from embryonic and adult brain as multipotent and self-renewing. However, NTN1 is dispensable for the proliferation of neurosphere forming progenitor cells and for their differentiation.

Netrin 1 contributes to vascular remodeling in the subventricular zone and promotes progenitor emigration after demyelination

“…Furthermore, NTN1 and its receptors have recently been detected in postnatal SVZ and RMS (Bradford et al, 2010;Hakanen et al, 2011). Here, we observed by western blot very low NTN1 expression in the SVZ of adult healthy mice but a strong and significant increase in SVZ a few days after CC demyelination.…”

“…Coimmunostaining experiments indicate that mainly type C cells and SVZ OPCs express NTN1 and that both neuronal and glial SVZ progenitors express the receptors DCC and neogenin, suggesting that they can respond to NTN1. Notably, NTN1 seems to play a role in the development of the olfactory bulb via the regulation of progenitor cell migration from the SVZ to the bulb (Murase and Horwitz, 2002;Hakanen et al, 2011). We showed here that lesioninduced emigration of neuronal progenitors from SVZ explants is significantly reduced by NTN1 blocking antibodies.…”

“…This receptor expression pattern is therefore not favorable to the repulsive hypothesis. It has recently been suggested that NTN1 might function in a cell-autonomous manner to promote the movement/ detachment/release of progenitor cells from embryonic forebrain explants (Hakanen et al, 2011). Interestingly, a recent study pointed out a dual effect of NTN1 on glioblastoma progression by promoting both angiogenesis and invasiveness (Shimizu et al, 2012).…”

Defects in neural guidepost structures and failure to remove leptomeningeal cells from the septal midline behind the interhemispheric fusion defects in Netrin1 deficient mice

“…Ntn1+/− mice were kept in a pure C57Bl6 background and crossed to generate Ntn1‐/‐ embryos. Both wild type and Ntn1+/− embryos were used as littermate controls when compared to Ntn1‐/‐ embryos, since no defects have been observed in Ntn1+/− animals (Salminen et al, 2000; Hakanen et al, 2011). Three mutant and control embryos were used for each stage for experiments except for the analysis in Fig.…”

From the periphery to the brain: Wiring the olfactory system

“…Its association with either DCC or some UNC5 receptors will lead to axon attraction or repulsion [177,178] Ntn2l Netrin-2-like protein precursor (See Netrin)…”