Abstract
The development of different brain regions involves the coordinated control of proliferation and cell fate specification along and across the neuraxis. Here, we identify Plxdc2 as a novel regulator of these processes, using in ovo electroporation and in vitro cultures of mammalian cells. Plxdc2 is a type I transmembrane protein with some homology to nidogen and to plexins. It is expressed in a highly discrete and dynamic pattern in the developing nervous system, with prominent expression in various patterning centres. In the chick neural tube, where Plxdc2 expression parallels that seen in the mouse, misexpression of Plxdc2 increases proliferation and alters patterns of neurogenesis, resulting in neural tube thickening at early stages. Expression of the Plxdc2 extracellular domain alone, which can be cleaved and shed in vivo, is sufficient for this activity, demonstrating a cell non-autonomous function. Induction of proliferation is also observed in cultured embryonic neuroepithelial cells (ENCs) derived from E9.5 mouse neural tube, which express a Plxdc2-binding activity. These experiments uncover a direct molecular activity of Plxdc2 in the control of proliferation, of relevance in understanding the role of this protein in various cancers, where its expression has been shown to be altered. They also implicate Plxdc2 as a novel component of the network of signalling molecules known to coordinate proliferation and differentiation in the developing nervous system.
Highlights
Expression of diffusible molecules controlling both proliferation and cell fate specification from defined organising centres in the developing nervous system underlies the coordination of differentiation and growth of different brain regions
Relative levels of the remaining part of the Plexin domain-containing 2 (Plxdc2) transcript in adult Plxdc2GFP mice were examined by real-time PCR, which illustrated a ten-fold decrease in the cerebella of Plxdc2-green fluorescent protein (GFP) homozygous mutants, when compared to wildtype animals (Fig. S2) indicating that in addition to interfering with protein translation and secretion, the alteration leads to greatly reduced transcript levels from the locus
No Mash1 or TUJI expression was observed in Embryonic neuroepithelial cells (ENCs) post treatment. These studies demonstrate that Plxdc2 is a novel mitogen for neural progenitors in the developing neural tube with the ability to alter normal patterns of neurogenesis
Summary
Expression of diffusible molecules controlling both proliferation and cell fate specification from defined organising centres in the developing nervous system underlies the coordination of differentiation and growth of different brain regions. Many important families of secreted molecules involved in these processes have been identified, including members of the bone morphogenetic protein (BMP), fibroblast growth factor (Fgf), insulin-like growth factor (Igf) and Wnt families as well as Sonic Hedgehog (Shh). The midbrain-hindbrain boundary (MHB), which expresses Wnt and Fgf, is one of several local signalling centres in the neuroepithelium which refines AP specification of the brain [1]. DV patterning is influenced by the floor plate, which expresses ventralising factors including sonic hedgehog (Shh) and nodal [2] and the roof plate at the dorsal midline, which expresses members of the BMP and Wnt families [3,4]. While advances have been made in understanding how growth and patterning are coordinated in the developing spinal cord [7] understanding of the coordination of these processes in the developing brain remains fragmented
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