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Nager syndrome is a rare human developmental disorder characterized by hypoplastic neural crest-derived craniofacial bones and limb defects. Mutations in SF3B4 gene, which encodes a component of the spliceosome, are a major cause for Nager. A review of the literature indicates that 45% of confirmed cases are also affected by conductive, sensorineural or mixed hearing loss. Conductive hearing loss is due to defective middle ear ossicles, which are neural crest derived, while sensorineural hearing loss typically results from defective inner ear or vestibulocochlear nerve, which are both derived from the otic placode. Animal model of Nager syndrome indicates that upon Sf3b4 knockdown cranial neural crest progenitors are depleted, which may account for the conductive hearing loss in these patients. To determine whether Sf3b4 plays a role in otic placode formation we analyzed the impact of Sf3b4 knockdown on otic development. Sf3b4-depleted Xenopus embryos exhibited reduced expression of several pan-placodal genes six1, dmrta1 and foxi4.1. We confirmed the dependence of placode genes expression on Sf3b4 function in animal cap explants expressing noggin, a BMP antagonist critical to induce placode fate in the ectoderm. Later in development, Sf3b4 morphant embryos had reduced expression of pax8, tbx2, otx2, bmp4 and wnt3a at the otic vesicle stage, and altered otic vesicle development. We propose that in addition to the neural crest, Sf3b4 is required for otic development, which may account for sensorineural hearing loss in Nager syndrome.
Fig. 1. Sf3b4 knockdown affects six1 and dmrta1 expression at the neurula stage. (a) Unilateral injection of increasing doses of Sf3b4MO (2 ng–20 ng) interfere with six1 and dmrta1 expression. RNA encoding the lineage tracer β-galactosidase was co-injected with Sf3b4MO to identify the injected side (red staining, right side in all panels). The arrows point to the affected placode areas. Anterior views, dorsal to top. (b) Quantification of six1 and dmrta1 ISH results. The numbers on the top of each bar indicate the number of embryos analyzed from three independent experiments.
Fig. 2. Sf3b4 knockdown affects a broad range of placode genes. (a) Unilateral injection of Sf3b4MO (10 ng) interfere with six1, dmrta1, foxi4.1 and pax8 expression. RNA encoding the lineage tracer β-galactosidase was co-injected with Sf3b4MO to identify the injected side (red staining, right side in all panels). The arrows point to the affected placode areas. pax8 is also expressed posteriorly in the prospective pronephros (asterisks). Anterior views, dorsal to top. (b) Quantification of the ISH results. The numbers on the top of each bar indicate the number of embryos analyzed from at least three independent experiments. Injection of a CoMO at the same concentration (10 ng) had no impact of the expression of these genes. ∗∗∗p<0.0001, Chi-squared test.
Fig. 3. Placode genes induction by noggin require Sf3b4. (a) Animal cap explants dissected from blastula stage embryos (NF stage 9) injected at the 2-cell stage with noggin mRNAs alone or in combination with Sf3b4MO were cultured for 8 h. (b) qRT-PCR analyses indicate that Sf3b4MO blocks placode (six1 and eya1) and neural plate (sox2) gene induction by Noggin in animal cap explants, and restores epidermal fate (krt12.4). Values are normalized to odc and presented as mean ± s.e.m.; (∗) p < 0.05 and (∗∗) p < 0.001 (Student’s t-test), from three independent samples.
Fig. 4. Sf3b4 knockdown affects otic vesicle gene expression. (a) Schematic representation of the expression pattern of pax8, tbx2, wnt3a, bmp4, and otx2 in the epithelium of the otic vesicle of NF stage 35 embryos. A, anterior; P posterior; D, dorsal; V, ventral. (b) In embryos injected with 10 ng of Sf3b4MO the regional otic expression of pax8, tbx2, wnt3a, bmp4, and otx2 is disrupted. RNA encoding the lineage tracer β-galactosidase was co-injected with Sf3b4MO to identify the injected side (red staining). The black arrows point to the otic expression of each gene on the control side and the white arrows to the corresponding affected areas on the Sf3b4MO-injected side. For orientation, the position of the eye is indicated (asterisks). Lateral views, anterior to left, dorsal to top. (c) Quantification of the ISH results. The numbers on the top of each bar indicate the number of embryos analyzed from three independent experiments.
Fig. 5. Sf3b4 knockdown affects otic vesicle development. (a) Serial sections (#1-anterior to #14-posterior) through a representative tbx2-stained embryo (NF stage 35) injected with 10 ng of Sf3b4MO. On the injected side (left side; double arrows), the size of the otic vesicle is reduced as compared to the control side (right side; single arrows). (b) The size of the otic vesicle (μm) was determined based on the number of sections (12 μm) required to cut the entire otic vesicle on control vs. injected sides. On average this represents 11.33 sections or 136 μm (control) vs. 6.77 sections or 81.33 μm (Sf3b4MO-injected). ∗p < 0.05 (Unpaired t-test with Welch’s correction), n=9.
Fig. 6. Sf3b4 knockdown affects olfactory gene expression. (a) Unilateral injection of Sf3b4MO (10 ng) interferes with dmrta1, ebf2 and six1 expression. RNA encoding the lineage tracer β-galactosidase was co-injected with Sf3b4MO to identify the injected side (red staining, right side in all panels). The arrows point to reduce gene expression in the olfactory epithelium. (b) Quantification of the ISH results. The numbers on the top of each bar indicate the number of embryos analyzed from two independent experiments. Injection of a CoMO at the same concentration (10 ng) had no impact of the expression of these genes. ∗∗∗p<0.0001, Chi-squared test.
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