GENETIC INTERACTIONS COORDINATING PIEBALD SPOTTING

协调花斑斑点的遗传相互作用

• 批准号: 6162562
• 负责人: W PAVAN
• 金额: --
• 依托单位: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6162562
• 关键词: complementary DNA; developmental genetics; gene expression; gene interaction; gene mutation; genetic mapping; genetic strain; laboratory mouse; messenger RNA; neural plate /tube; northern blottings; nucleic acid sequence; pigmentation; receptor expression

The black and white spotting pattern observed in piebald (s) mice results from abnormal neural crest development due to a mutation in endothelin receptor B (EDNRB). The severity and distribution of the pigment patterns are vastly different in two inbred strains carrying the s mutation (Mayers/s and C3H s/s). We hypothesized that additional genes may be responsible for coordinating the differences in patterning observed. Quantitative genetic analysis of backcross progeny from these two strains identified four genetic modifiers located on Chromosomes 2, 5, 8 and 10. The modifier on Chromosome 10 increases the dorsal spotting 2-fold more than ventral spotting (19.7% vs 9.1%, p < 0.0001), suggesting this modifier has spatial or temporal affects on pigment patterning. Analysis of mapping data implicates Steel (mast cell growth factor) as a candidate gene for this locus. Sequence comparison of cDNA isolates did not indicate any differences in the coding region, however differences in the level of steady state mRNA in adult tissues was observed by Northern blot analyses. Comparison of the genomic structure of the Steel gene demonstrated 12/12 restriction enzymes showing differences in the size of DNA fragments, however no differences were observed in two un-linked genes, EDNRB and endothelin 3. These results suggest the increased dorsal spotting observed in the Mayer strain of s mice is due to a mutation that alters the Steel expression pattern.We have tested this hypothesis by using crosses between the Mayer strain and Steel null mice. Consistent with our hypothesis, the Mayer allele at Steel cannot complement a Steel null mutation and results in increased dorsal spotting. Future studies using embryonic reconstitution experiments and expression pattern studies will also be explored to determine the molecular alterations and interactions at each modifier locus.

在Piebald（S）小鼠中观察到的黑白斑点模式结果 由于内皮素突变引起的异常神经rest发育 受体B（EDNRB）。色素模式的严重程度和分布 携带S突变的两个近交菌株中有很大的不同 （Mayers/S和C3H S/S）。我们假设其他基因可能是 负责协调观察到的图案差异。 从这两种菌株的后代后代的定量遗传分析 确定了位于染色体2、5、8和10上的四个遗传修饰符。 染色体10上的修饰符增加了背斑的2倍 比腹侧斑点（19.7％vs 9.1％，p <0.0001），这表明了这一点 修饰符对色素模式具有空间或时间影响。分析 映射数据的含义（肥大细胞生长因子）作为候选者 这个基因座的基因。 cDNA分离株的序列比较没有 表示编码区域的任何差异，但是 通过北印迹观察到成人组织中稳态mRNA的水平 分析。钢基因基因组结构的比较 展示的12/12限制性酶显示出大小的差异 在DNA片段中，但是在两个未连接中没有观察到差异 基因，EDNRB和内皮素3。这些结果表明背侧增加 在S小鼠的Mayer菌株中观察到的发现是由于突变引起的 改变了钢表达模式。我们已经通过 使用Mayer应变和钢无效小鼠之间的杂交。持续的 有了我们的假设，钢的Mayer等位基因无法补充钢 无效突变并导致背侧斑点增加。未来的研究 使用胚胎重构实验和表达模式研究 还将探讨以确定分子改变和 每个修饰符基因座的相互作用。