Olfactory bulb development is altered in small-eye (Sey) mice

Abstract

Small-eye (Sey) is a spontaneous, semidominant murine mutation that results from a point mutation in the Pax-6 gene. Both the eyes and the olfactory system fail to develop in homozygotes and these animals die neonatally. Heterozygotes (Sey/+) have different degrees of eye abnormalities including decreased lens size and cataracts. In the present study, we examined whether one mutated allele of Pax-6 also affects olfactory system development. By 42 days of age, main olfactory bulb volume was significantly decreased in Sey/+ animals compared with wild-type littermates, and this effect was even more dramatic in 70-day-old animals. In contrast, there was no effect on accessory olfactory bulb, olfactory epithelial, or vomeronasal organ development at any age in Sey/+ animals, demonstrating the specificity of the effect. In the main olfactory bulb, the largest differences in laminar volume were found in the glomerular and granule cell layers. These layers contain the olfactory bulb interneurons, and a subpopulation of these cells were found to be Pax-6 immunoreactive. Examination of the neurochemical consequences of this mutation showed that the number of both tyrosine hydroxylase (TH)- and gamma-aminobutyric acid (GABA)-immunoreactive profiles were dramatically decreased in Sey/+ animals as compared with controls. In contrast, neither calretinin nor calbindin immunoreactivity was affected by this mutation. Dual-labeling immunohistochemistry showed that nearly all TH-immunoreactive cells and a subpopulation of GABA-immunoreactive cells coexpressed Pax-6. However, calretinin- and calbindin-immunoreactive cells were not Pax-6 immunopositive. These data indicate that two normal alleles of Pax-6 are required for normal olfactory bulb development and, as part of this effect, this gene may be involved in the development of specific neurotransmitter systems.

Dlx-Dependent and -Independent Regulation of Olfactory Bulb Interneuron Differentiation

“…Expression of Pax6 marks at least three cell populations in and around the OB: VZ cells in the OB, OB neurons, and scattered cells in the anterior olfactory nuclei (AON) (Stoykova and Gruss, 1994;Dellovade et al, 1998;Lopez-Mascaraque and de Castro, 2002;Hack et al, 2005;Kohwi et al, 2005). Among these Pax6 ϩ cells, the Dlx1&2 Ϫ/Ϫ mutation appears to selectively eliminate the OB interneurons (Fig.…”

“…In the absence of Dlx1&2, the mouse prenatal OB nearly lacks all expression of essential regulators of GABAergic function (glutamic acid decarboxylase and vesicular GABA transporter). Also, the OB mantle layer nearly lacks expression of several transcription factors, such as ER81, Pax6, and Sp8; these genes are either required or implicated in OB interneuron development (Dellovade et al, 1998;Stenman et al, 2003;Hack et al, 2005;Kohwi et al, 2005;Waclaw et al, 2006).…”

“…In addition to the early role of Pax6 in patterning the OB anlage (Anchan et al, 1997;Jimenez et al, 2000;Nomura and Osumi, 2004;Nomura et al, 2006), this paired-homeobox gene has a later role for generating dopaminergic periglomerular interneurons and is implicated in regulating development of superficial granule cells (Dellovade et al, 1998;Hack et al, 2005;Kohwi et al, 2005). The Sp8 zinc-finger gene is expressed in and required for the differentiation of GABA-positive (GABA ϩ ) and calretinin ϩ periglomerular cells (Waclaw et al, 2006).…”

Role of a transcription factor Pax6 in the developing vertebrate olfactory system

“…Transplantation studies of the neuronal progenitor cells also revealed the cell-autonomous requirements of Pax6 in differentiation of the dopaminergic PGCs (Kohwi et al 2005). Furthermore, the number of dopaminergic PGCs is decreased in Pax6 heterozygous mutant mice (Dellovade et al 1998;Kohwi et al 2005). We recently identified that the number of other PGC subtypes is also reduced in the olfactory bulb of Pax6 heterozygous mutant (H. Haba, T. Nomura and N. Osumi unpubl.…”

Un microARN régule la production de neurones dopaminergiques dans le cerveau antérieur

“…Une protéine clé pour la génération des neurones dopaminergiques du cerveau antérieur est le facteur de transcription Pax6 (paired box 6) [4,5]. De plus, il a été montré que l'action de ce facteur est clairement dépendante de sa concentration, notamment dans sa fonction de déterminant dopaminergique [6]. Il doit donc nécessairement exister des méca-nismes qui régulent finement l'expression de cette protéine dans les cellules.…”