Murcia Crystal L, Gulden Forrest O, Cherosky Natalie A, Herrup Karl
Alzheimer Research Laboratory, Department of Neuroscience, Case Western Reserve University, Cleveland, OH 44106, USA.
Brain Res. 2007 Apr 6;1140:170-8. doi: 10.1016/j.brainres.2006.06.076. Epub 2006 Aug 1.
The mouse Engrailed genes, En1 and En2, play an important role in the development of the cerebellum from its inception at the mid/hindbrain boundary in early embryonic development through cell type specification events and beyond. In the absence of En1, the cerebellum and caudal midbrain fail to develop normally--a phenotype that we have previously reported to be strain dependent. On the 129/S1 strain background, En1 null alleles lead to mid/hindbrain failure, whereas on the C57BL/6 background, En1 deficiency is compatible with near normal cerebellar development. We have pursued this dramatic effect of genetic background by performing a genetic modifier screen through F1 backcross and F1 intercross matings. The backcross has yielded two strong candidate intervals with suggestive linkage to a third region. Moreover, variations in rescue frequency among subgroups within the backcross indicate gender and parent of origin influences on rescue penetrance. The intercross data reveal locus heterogeneity of the En1 modifiers, with more than one compliment of C57BL/6 and 129/S1 alleles capable of mediating the rescue phenotype. These findings highlight the complexity and plasticity of gene networks involved in brain development.
小鼠的Engrailed基因，即En1和En2，在小脑发育过程中起着重要作用，从小脑在胚胎发育早期中脑/后脑边界处开始形成，历经细胞类型特化等过程直至后续阶段。在缺乏En1的情况下，小脑和尾侧中脑无法正常发育——我们之前报道过这种表型具有品系依赖性。在129/S1品系背景下，En1无效等位基因会导致中脑/后脑发育失败，而在C57BL/6背景下，En1缺陷与近乎正常的小脑发育是相容的。我们通过F1回交和F1杂交交配进行遗传修饰筛选，来探究这种遗传背景的显著影响。回交产生了两个与第三个区域有提示性连锁的强候选区间。此外，回交亚组间拯救频率的差异表明性别和起源亲本对拯救外显率有影响。杂交数据揭示了En1修饰基因的位点异质性，有不止一种C57BL/6和129/S1等位基因组合能够介导拯救表型。这些发现凸显了参与大脑发育的基因网络的复杂性和可塑性。
