Role of Growth/Differentiation factor (GDF) 15 in the regulation of embryonic neural precursors

Abstract

TGF-b superfamily members play important roles in the regulation of multiple aspects of neural stem cell behaviour. Growth/differentiation factor 15 (GDF15), a new member of this superfamily recently cloned and characterized by our lab and others, has been shown to be expressed at low levels in the rodent brain (Bottner(a) et al., 1999) and to be particularly localised in neurogenic areas as the sub-ventricular zone (SVZ) of the lateral ventricles (Schober et al., 2001). As a follow up of this observation, in this study I investigated the possibility that GDF15 may play a role in the regulation of neural precursor behaviour during brain development. In this work, I first demonstrated that GDF15 is expressed in neurogenic areas of the mouse brain during development and that neural precursor cells (NPCs) represent the main source of GDF15. I next analysed a GDF15 KO / lacZ KI mouse line developed in our lab to investigate the effect of lack of GDF15 expression on NPCs. Comparative analysis between NPCs isolated from WT and GDF15-/- mice revealed that absence of GDF15 leads to a decrease in the expression of EGFR in NPCs without affecting the total number of primary clone forming precursors neither in the ganglionic eminence (GE) nor in the Hippocampus. However, in the GE absence of GDF15 alters the timing of cell cycle exit of secondary progenitors differentiating from primary NPCs. These observations in vitro were also confirmed in vivo. Analysis of brain neurogenic areas by immunohistochemistry showed that lack of GDF15 induces a downregulation of EGFR expression in neural precursor cells in both hippocampus and GE, leading to a decrease in neural precursor proliferation in the hippocampus but not affecting the proliferation of primary precursors in the GE. Instead, I found that in this region in vivo as in vitro, in the absence of GDF15 expression, secondary precursors are going extra round of proliferation leading to an increase in mash1 immunopositive cells in the SVZ and in the lateral GE. Thus, this is the first study which describes GDF15 as a new regulatory molecule of the neuronal lineage in the developing mouse telencephalon.