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Results: 7

1.
Figure 5

Figure 5. Shh pathway gene expression in the palatal shelves of WT and Gas1–/– mice. . From: Gas1 is a modifier for holoprosencephaly and genetically interacts with sonic hedgehog .

(AD) At E13.5, Shh was expressed in the epithelium of WT and Gas1–/– palatal shelves. (E and F) Ptc1 was expressed throughout the epithelium and mesenchyme of WT shelves, in addition to isolated regions in the palatal bend mesenchyme (F, arrow). (G and H) In contrast, Gas1–/– palatal shelves had reduced Ptc1 expression, which failed to extend along their length and was lost in the palatal bend mesenchyme (H, arrow). Scale bar: 250 μm.

Maisa Seppala, et al. J Clin Invest. 2007 June 1;117(6):1575-1584.
2.
Figure 4

Figure 4. Palatogenesis in WT and Gas1–/– mice. . From: Gas1 is a modifier for holoprosencephaly and genetically interacts with sonic hedgehog .

(A and B) Scanning electron microscopy demonstrating that palate development was complete in WT mice at P0 (A), while there was a full-penetrance cleft of the secondary palate in affected Gas1–/– mice at the same time point (B). (C and D) Histological analysis showed comparable morphology of the palatal shelves at E13.5 in WT and Gas1–/– embryos. (E and F) At E15.5, while the shelves rose above the tongue and fused in the midline in the WT embryos, fusion failed to occur in affected Gas1–/– embryos. Scale bar: 1.25 mm (A and B); 500 μm (CF).

Maisa Seppala, et al. J Clin Invest. 2007 June 1;117(6):1575-1584.
3.
Figure 6

Figure 6. Cell proliferation in the developing palate of WT and Gas1–/– mice. . From: Gas1 is a modifier for holoprosencephaly and genetically interacts with sonic hedgehog .

(AF) BrdU analysis of E13.5 WT and Gas1–/– palatal shelves. In B, the upper and lower boxes identify the area of mesenchymal cells counted in the palatal bend and apex, respectively; upper and lower dotted lines represent the regions of epithelial cells counted at the bend and apex, respectively. Scale bar: 125 μm. (G and H) Percentage of BrdU incorporation for each area assayed. Proliferation rates were significantly reduced in epithelium of the middle and posterior apex and mesenchyme of the middle and posterior apex and bend. a, anterior palate; m, middle palate; p, posterior palate. Data are mean ± SD. n = 4 mice per group analyzed for each embryonic stage (total of 45 WT and 55 Gas1–/– sections counted). *P < 0.05 versus WT.

Maisa Seppala, et al. J Clin Invest. 2007 June 1;117(6):1575-1584.
4.
Figure 2

Figure 2. Shh pathway gene expression in the craniofacial region of WT and Gas1–/– mice. . From: Gas1 is a modifier for holoprosencephaly and genetically interacts with sonic hedgehog .

(A, B, F, and G) At E10.5 and E11.5, sagittal sections demarcated Shh in the pharyngeal endoderm, diencephalon, and facial ectoderm of WT embryos. (C, D, H, and I) Ptc1 and Gli1 demonstrated a gradient of transcriptional activity across these regions in response to signaling. (E and J) In contrast, Gas1 was expressed at a distance from the source of Shh transcription, in a partially overlapping domain with Ptc1 and Gli1, at their peripheral margins. (KR) In Gas1–/– embryos at both E10.5 and E11.5, there was a marked reduction in the domain of both Ptc1 (M and Q) and Gli1 (N and R) expression within the frontonasal (black arrows) and mandibular processes (blue arrows) compared with that of WT embryos (compare with respective arrows in C, D, H, and I), while Shh expression was normal in Gas1–/– compared with WT embryos (B and G) at both stages. di, diencephalon; fe, facial ectoderm; fnp, frontonasal process; md, mandibular process; ne, neural ectoderm; pe, pharyngeal endoderm; rp, Rathke’s pouch; t, telencephalon. Scale bar: 200 μm.

Maisa Seppala, et al. J Clin Invest. 2007 June 1;117(6):1575-1584.
5.
Figure 3

Figure 3. The frontonasal region is reduced in Gas1–/– embryos. . From: Gas1 is a modifier for holoprosencephaly and genetically interacts with sonic hedgehog .

(A and B) At E12.5, histological analysis revealed a lack of transverse development in the maxillary incisor region in Gas1–/– compared with WT embryos (double arrows). In addition, the vomeronasal organ surrounded by the early paraseptal cartilage (A, arrow) failed to develop in Gas1–/– mice. (CF) This reduced development caused fusion of the early incisor placodes and continuous expression of Shh across the frontonasal region of Gas1–/– mice. (C and D) Radioactive section in situ hybridization. (E and F) Whole-mount in situ hybridization. (G and H) Ptc1 expression was reduced in the frontonasal region of Gas1–/– compared with WT embryos. (I and J) In perinatal WT embryos, the bilateral maxillary incisor teeth formed in their normal positions adjacent to the nasal capsule, while in Gas1–/– mice, a single enlarged maxillary incisor crown was present, representing fusion between 2 separate tooth germs. The paraseptal cartilage, which failed to form in Gas1–/– mice, is denoted by an arrow. i, premaxillary incisor. Scale bar: 250 μm (AD, G and H); 500 μm (E and F); 750 μm (I and J).

Maisa Seppala, et al. J Clin Invest. 2007 June 1;117(6):1575-1584.
6.
Figure 1

Figure 1. Craniofacial defects associated with the perinatal Gas1–/– skull. . From: Gas1 is a modifier for holoprosencephaly and genetically interacts with sonic hedgehog .

(A) Comparison of WT and Gas1–/– skulls differentially stained for bone (red) and cartilage (blue) demonstrated the reduced size of the Gas1–/– skull. (B) Norma basalis of WT and Gas1–/– skulls. Blue arrows indicate the absence of optic pillars in the Gas1–/– mouse; yellow arrows highlight the Gas1–/– cleft palate; black arrow indicates fenestration of the Gas1–/– neurocranial base; green arrows indicate dysmorphic ectotympanic rings; and white arrows denote absence of the hypoglossal foramen. (C and D) Magnified norma basalis views of the maxillary and premaxillary palate of WT (C) and 2 Gas1–/– (D) neonates without fully cleft palates. Red arrows highlight the morphologic range of fused incisors in Gas1–/– mice; green arrows indicate the range of midline hypoplasia in premaxillary palatal shelves and paraseptal cartilages; and yellow arrows show the developing maxillary palatal shelves. (EL) Comparison of WT (E) and Gas1–/– (FL) middle ear skeletal elements demonstrating the range of dysmorphology evident in Gas1–/– mice. Outlined are the styloid process (green), stapes (orange), incus (yellow), and malleus (purple) in WT mice. Green arrows indicate tympanohyal segments; pink arrows indicate stylohyal segments; purple arrows indicate the mallei; yellow arrows indicate the incuses; blue arrows highlight the gonials; orange arrows highlight the stapes; red arrows indicate the ectotympanics; black arrows indicates ectopic cartilage between the stapes, styloid process, and ectotympanic; and white arrows indicate hypoglossal foreman. Exemplified in K is the fusion of the stapes to the otic capsule. Original magnification, ×1.8 (C and D); ×2.3 (E and F); ×1.3 (GL).

Maisa Seppala, et al. J Clin Invest. 2007 June 1;117(6):1575-1584.
7.
Figure 7

Figure 7. Demonstration of a genetic interaction between Gas1 and Shh. . From: Gas1 is a modifier for holoprosencephaly and genetically interacts with sonic hedgehog .

(AD) Comparison of Gas1+/–Shh+/–, Gas1–/–Shh+/+, and 2 Gas1–/–Shh+/– perinatal skulls. The left 3 mice were littermates. (A) Norma basalis. The black line aligns the skulls, which were photographed at the same magnification. (B) Norma lateralis. (C) Dentaries of Gas1+/–Shh+/–, Gas1–/–Shh+/+, and Gas1–/–Shh+/– perinates. Notably, the Gas1–/–Shh+/– perinates, in addition to midline fusion and a single incisor, exhibited what appears to be a duplicated proximal dentary that includes a secondary cartilage-containing condylar process (black arrows) and an alveolus containing an ectopic molar (green arrow). White arrowhead indicates truncation and proximal bifurcation of Meckel’s cartilage. Original magnification, ×4. (D) Calvaria of Gas1+/–Shh+/–, Gas1–/–Shh+/+, and Gas1–/–Shh+/– skulls. Black arrowheads highlight the loss of a patent coronal suture in the calvarium of the Gas1–/–Shh+/– skull. (E) Histological sections of the developing ectopic molar (red arrow) and dentary. MC, Meckel’s cartilage; oc, otic capsule. (F) Comparison of WT and Gas1–/–Shh+/– middle ears. Outlined in the WT image are styloid process (green), stapes (orange), incus (yellow), and malleus (purple). Yellow arrows highlight the vestigial stapes; green arrows indicate the ectopic preotic pillar running from the neurocranial base to the otic capsule; red arrows indicate persistent cartilage of the ala temporalis; blue arrows indicate changes at the squamosal; black arrows indicate the ectopic condyles; dotted yellow line denotes axis of symmetry. Original magnification, ×2.

Maisa Seppala, et al. J Clin Invest. 2007 June 1;117(6):1575-1584.

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