J Clin Invest. 2014 Mar;124(3):1214-27. doi: 10.1172/JCI72466.
The olfactory bulb (OB) receives odor information from the olfactory epithelium and relays this to the olfactory cortex. Using a mouse model, we found that development and maturation of OB interneurons depends on the zinc finger homeodomain factor teashirt zinc finger family member 1 (TSHZ1). In mice lacking TSHZ1, neuroblasts exhibited a normal tangential migration to the OB; however, upon arrival to the OB, the neuroblasts were distributed aberrantly within the radial dimension, and many immature neuroblasts failed to exit the rostral migratory stream. Conditional deletion of Tshz1 in mice resulted in OB hypoplasia and severe olfactory deficits. We therefore investigated olfaction in human subjects from families with congenital aural atresia that were heterozygous for TSHZ1 loss-of-function mutations. These individuals displayed hyposmia, which is characterized by impaired odor discrimination and reduced olfactory sensitivity. Microarray analysis, in situ hybridization, and ChIP revealed that TSHZ1 bound to and regulated expression of the gene encoding prokineticin receptor 2 (PROKR2), a G protein–coupled receptor essential for OB development. Mutations in PROKR2 lead to Kallmann syndrome, characterized by anosmia and hypogonadotrophic hypogonadism. Our data indicate that TSHZ1 is a key regulator of mammalian OB development and function and controls the expression of molecules involved in human Kallmann syndrome.
嗅球（OB）从嗅上皮接收气味信息，并将其传递到嗅皮层。使用小鼠模型，我们发现 OB 中间神经元的发育和成熟依赖于锌指同源结构域因子茶袖锌指家族成员 1（TSHZ1）。在缺乏 TSHZ1 的小鼠中，神经前体细胞表现出正常的切线迁移到 OB；然而，到达 OB 后，神经前体细胞在放射状维度上分布异常，许多未成熟的神经前体细胞未能退出嗅球前迁移流。在小鼠中条件性缺失 Tshz1 导致 OB 发育不良和严重的嗅觉缺陷。因此，我们研究了携带 TSHZ1 功能丧失突变的先天性耳聋家系的人类受试者的嗅觉。这些个体表现出嗅觉减退，其特征是气味辨别受损和嗅觉敏感性降低。微阵列分析、原位杂交和 ChIP 显示 TSHZ1 结合并调节编码促动力素受体 2（PROKR2）的基因的表达，PROKR2 是 OB 发育所必需的 G 蛋白偶联受体。PROKR2 的突变导致 Kallmann 综合征，其特征为嗅觉丧失和促性腺激素分泌不足性性腺功能减退症。我们的数据表明，TSHZ1 是哺乳动物 OB 发育和功能的关键调节剂，控制参与人类 Kallmann 综合征的分子的表达。
