Cranial anomaly of homozygous rSey rat is associated with a defect in the migration pathway of midbrain crest cells

Abstract

Craniofacial development of vertebrates depends largely on neural crest contribution and each subdomain of the crest-derived ectomesenchyme follows its specific genetic control. The rat small eye (rSey) involves a mutation in the Pax-6 gene and the external feature of rSey homozygous embryos exhibits craniofacial defects in ocular and frontonasal regions. In order to identify the mechanism of craniofacial development, we examined the cranial morphology and migration of cephalic crest cells in rSey embryos. The chondrocranial defects of homozygous rSey embryos primarily consisted of spheno-orbital and ethmoidal anomalies. The former defects appeared to be brought about by the lack of the eye. In the ethmoid region, the nasal septum and the derivative of the medial nasal prominence were present, while the rest of the nasal capsule, as well as the nasal and lachrymal bones, were totally absent except for a pair of cartilaginous rods in place of the nasal capsule. This suggests that the primary cranial defect is restricted to the lateral nasal prominence derivatives. Dil labeling revealed the abnormal migration of crest cells specifically from the anterior midbrain to the lateral nasal prominence in homozygous rSey embryos. Pax-6 was not expressed in the crest cells but was strongly expressed in the frontonasal ectoderm. To determine whether or not this migratory defect actually resides in environmental cues, normal midbrain crest cells from wild-type embryos were labeled with Dil and were orthotopically injected into host rSey embryos. Migration of the donor crest cells into the lateral nasal prominence was abnormal in homozygous host embryos, while they migrated normally in wild-type or heterozygous embryos. Therefore, the cranial defects in rSey homozygous embryos are due to inappropriate substrate for crest cell migration towards the lateral nasal prominence, which consistently explains the cranial morphology of homozygous rSey embryos.

Mouse Fbw7/Sel-10/Cdc4 Is Required for Notch Degradation during Vascular Development

“…Whole mount in situ hybridization was performed as described previously (29). The Hes5, Hes7, Uncx4.1, Hey1, Hey2, and HeyL riboprobes, each corresponding to the entire open reading frame of the corresponding cDNA, were synthesized with a DIG RNA labeling kit.…”

Study of Pax6 mutant rat revealed the association between upper incisor formation and midface formation

“…A typical feature of the homozygote of these mice and rats is the lack of eyes and nose (Hogan et al, 1988;Hill et al, 1991;Fujiwara et al, 1994;Grindley et al, 1995), which is attributed to defective induction of the lens and nasal placodes that express the Pax6 gene (Grindley et al, 1995). The appearance of other craniofacial abnormalities in the homozygotes, such as the supernumerary upper incisors (Kaufman et al, 1995;OsumiYamashita et al, 1997) or cartilagenous "spur" (Quinn et al, 1997;Osumi-Yamashita et al, 1997), depends on genetic background rather than allele type in mouse strains (Quinn et al, 1997). Pax6 function in optic and olfactory system formation has been extensively studied (for review, see Treisman, 2004;Lang, 2004;Kozmik, 2005).…”

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

“…In Pax6 homozygous embryos, the migrating NCDCs cannot invade into the front-nasal mass (Matsuo et al 1993;Osumi-Yamashita et al 1997). The abnormal migration is due to non-cell autonomous defects in the migrating NCDCs (Osumi-Yamashita et al 1997). Recent studies also indicated that HNK-1 carbohydrate epitope and the GlcAT-P gene that encodes an enzyme for the synthesis of the HNK-1 epitope are ectopically expressed in the facial ectoderm of the Pax6 mutant rat (Nagase et al 2001(Nagase et al , 2003.…”

“…Compared with WT, the expression levels of fgfr1 and fgfr3 are severely reduced in the rSey 2 /rSey 2 telencephalon. The experimental procedure of in situ hybridization was described previously (Osumi-Yamashita et al 1997). Bars, 100 µm (A-F).…”