GENETIC INTERACTIONS COORDINATING PIEBALD SPOTTING Pavan, W

在斑斑小鼠中观察到的黑色和白色斑点模式是由于内皮素受体B （EDNRB）突变引起的神经嵴发育异常所致。在携带s突变的两个近交系（Mayers/s和C3H s/s）中，色素模式的严重程度和分布有很大不同。我们假设其他基因可能负责协调所观察到的模式差异。对这两个菌株回交后代进行定量遗传分析，鉴定出4个遗传修饰子位于染色体2、5、8和10上。10号染色体上的修饰子使背侧斑点比腹侧斑点增加2倍（19.7%比9.1%,p < 0.0001），表明该修饰子对色素模式有空间或时间影响。定位数据分析暗示Steel（肥大细胞生长因子）是该位点的候选基因。cDNA分离物的序列比较未发现编码区有任何差异，但通过Northern blot分析，在成年组织中观察到稳态mRNA水平的差异。比较Steel基因的基因组结构，发现12/12限制性内切酶在DNA片段大小上存在差异，但两个非连锁基因EDNRB和内皮素3没有差异。这些结果表明，在5只小鼠的Mayer品系中观察到的背部斑点增加是由于改变了Steel表达模式的突变。我们已经通过使用Mayer菌株和Steel null小鼠之间的杂交来验证这一假设。与我们的假设一致，Steel的Mayer等位基因不能补充Steel null突变，并导致背部斑点增加。未来的研究还将利用胚胎重构实验和表达模式研究来确定每个修饰位点的分子改变和相互作用。-生物技术研究、癌症研究、消化系统疾病、基因定位（非人类）、神经科学、儿科研究；

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. - biotechnology research, cancer research, digestive diseases, gene mapping(non-human), neuroscience, pediatric research,