The role of Dlx homeogenes in early development of the olfactory pathway

Abstract

Development of the olfactory pathway requires interaction between cells and signals of different origin. Olfactory receptor neurons (ORN) in the olfactory placodes (OP) extend axons towards the forebrain (FB); with innervation taking place at a later time following degradation of the basement membrane. Cells from the OP migrate along ORN axons and differentiate into various elements, including ensheathing and Gonadotropin Releasing Hormone (GnRH)+ cells. The importance of the olfactory connection and migration is highlighted by the severe endocrine phenotype in Kallmann's patients who lack this migratory pathway. Little is known about the genetic control of intrinsic ORN properties. Inactivation of the distalless-related Dlx5 prevents connections between ORNs and FB. Using a grafting approach we show that misguidance and lack of connectivity is due to intrinsic defects in ORN neurites and migratory cells (MgC), and not to environmental factors. These data point to a cell-autonomous function of Dlx5 in providing ORN axons with their connectivity properties. Dlx5 also marks a population of early MgC that partly overlaps with the GnRH+ population. In the absence of Dlx5 MgCs of the Dlx5+ lineage migrate, associated with PSA-NCAM+ axons, but fail to reach the FB as a consequence of the lack of axonal connection and not an inability to migrate. These data suggests that Dlx5 is not required to initiate migration and differentiation of MgCs.

Neural Crest and Ectodermal Cells Intermix in the Nasal Placode to Give Rise to GnRH-1 Neurons, Sensory Neurons, and Olfactory Ensheathing Cells

“…These findings confirm that GnRH-1 neurons are derived from two different lineages, with the majority originating from ectodermal cells and the remaining fraction of NC origin. These data are consistent with a previous report in which Dlx5 expression was found in 70% of migratory GnRH-1 neurons (Merlo et al, 2007). In fact, heterogeneity has been described within GnRH-1 expressing neurons at both the morphological and molecular level (Wray and Hoffman, 1986; Jasoni et al, 2005; Cottrell et al, 2006; Constantin et al, 2009; Jasoni et al, 2009; Klenke et al, 2010).…”

“…However, localization and lineage of GnRH-1 progenitors is still unclear. A placodal, non-placodal ectodermal, and NC origin have all been proposed for these cells (el Amraoui and Dubois, 1993; Whitlock et al, 2003; Merlo et al, 2007; Metz and Wray, 2010). …”

The Src Homology 2 Domain Protein Shep1 Plays an Important Role in the Penetration of Olfactory Sensory Axons into the Forebrain

“…A number of transcriptional regulators have been shown to regulate olfactory bulb innervation by OSN axons and development, including the homeodomain transcription factors Dlx5 (Levi et al, 2003; Merlo et al, 2007) and Emx2 (Yoshida et al, 1997), the zinc finger transcription factor Klf7 (Laub et al, 2005), and the zinc-finger transcriptional repressor Fezf1 (Hirata et al, 2006; Watanabe et al, 2009). Similar to Shep1 knockout mice, the basement membrane surrounding the olfactory bulb lacks fenestrations in the Dlx5 knockout mice (Merlo et al, 2007).…”

“…Similar to Shep1 knockout mice, the basement membrane surrounding the olfactory bulb lacks fenestrations in the Dlx5 knockout mice (Merlo et al, 2007). In addition, Fezf1-deficient OSN axons fail to penetrate the basal lamina surrounding the olfactory bulb and loss of Fezf1 also impairs axonal growth from olfactory epithelium explants embedded in Matrigel (Watanabe et al, 2009).…”

BMP-Mediated Functional Cooperation between Dlx5;Dlx6 and Msx1;Msx2 during Mammalian Limb Development

“…Third, in vitro the Dlx and Msx proteins compete for the same DNA binding sites, form heterodimers via their homeodomain and reciprocally inhibit their transcriptional activities [44], due to the high degree of homology of their homeodomains [37], [43], [45], [46], [47]. However, current literature suggest that Dlx and Msx proteins have distinct functions: Msx1 and Msx2 are known to control cell proliferation and differentiation in a variety of cell types [48], [49], [50], [51], while Dlx genes are implicated in the differentiation of specific cell lineages, such as forebrain interneurons [52], [53], [54], olfactory receptor neurons [55], osteoblasts [35], [56], and the AER and ectoderm [29], [30], [57], [58]. Notably, Dlx and Msx genes have been shown to cooperate only in specific cases [59], [60], [61], but not at all sites where they are co-expressed.…”