A Balance of BMP and Notch Activity Regulates Neurogenesis and Olfactory Nerve Formation

Esther Maier,Lena Gunhaga,Jonas Von Hofsten,Hanna Nord,Christos Samakovlis

doi:10.1371/journal.pone.0017379

Abstract

Although the function of the adult olfactory system has been thoroughly studied, the molecular mechanisms regulating the initial formation of the olfactory nerve, the first cranial nerve, remain poorly defined. Here, we provide evidence that both modulated Notch and bone morphogenetic protein (BMP) signaling affect the generation of neurons in the olfactory epithelium and reduce the number of migratory neurons, so called epithelioid cells. We show that this reduction of epithelial and migratory neurons is followed by a subsequent failure or complete absence of olfactory nerve formation. These data provide new insights into the early generation of neurons in the olfactory epithelium and the initial formation of the olfactory nerve tract. Our results present a novel mechanism in which BMP signals negatively affect Notch activity in a dominant manner in the olfactory epithelium, thereby regulating neurogenesis and explain why a balance of BMP and Notch activity is critical for the generation of neurons and proper development of the olfactory nerve.

Highlights

The sense of smell among animals is used for food search and evaluation, localization of predators or preys, and for chemical detection of individuals
To examine the effects of bone morphogenetic protein (BMP) and Notch signaling on early neurogenesis and the initial formation of the olfactory nerve, we electroporated stage 12/13 chick embryos, prior to the onset of neurogenesis [6], in the olfactory placodal region to transfer a control green fluorescent protein (GFP) vector alone or together with the following constructs; I) a dominant negative MAMLI vector, that acts as an inhibitor of Notch signaling [18], II) a caNotch1-intracellular domain (ICD) vector containing a constitutively active Notch receptor [19], III) a Noggin vector, which act as a BMP inhibitor [20], IV) a constitutively active BMP receptor, Alk6 (Bmpr1b), vector [21]
In all Alk6-electroporated embryos (n = 8), where BMP signaling was elevated, the olfactory nerve was reduced in thickness (Fig. 1E,e), and a similar phenotype was observed in Noggin-transfected embryos (3/5) (Fig. 1F,f)

Summary

Introduction

The sense of smell among animals is used for food search and evaluation, localization of predators or preys, and for chemical detection of individuals. Coincident with the invagination of the placode into the olfactory pit, the majority of the earliest forming neurons migrate away from the olfactory epithelium, and are often referred to as epithelioid cells or migratory mass [1,4,5,6,7]. The function of these early-delaminating neurons remains unclear, they have been suggested to perforate the olfactory epithelial basal lamina creating openings later utilized by emerging olfactory axons [4], and to build up the olfactory nerve tract [5,7]. Despite the morphological characterisation of early events in olfactory nerve formation, little is known about how extrinsic signals control the early events of neurogenesis and the generation of the first migratory neurons from the olfactory sensory epithelium

Methods

Results

Conclusion