YAP and TAZ loss of function in the neural crest broadly affects olfactory ensheathing cells, olfactory-vomeronasal neurons, but not GnRH-1 neuronal migration.

Olfactory Ensheathing Cells (OECs) originate from the neural crest and are critical for bundling olfactory axons to the brain. Their development is vital for the migration of Gonadotropin-Releasing Hormone-1 (GnRH-1) neurons, which are essential for puberty and fertility. OECs are of particular interest for potential treatments of central nervous system lesions, though their development is not fully understood. Our single-cell RNA sequencing of mouse embryonic nasal tissues suggests that OECs and Schwann cells share a common origin from Schwann Cell Precursors (SCPs). However, OECs and SCs have significant genetic differences. Wnt1 is highly expressed in pre-migratory neural crest cells, while Sox10 expression occurs later and is lost in most derivatives, except for nasal cartilage, SCPs, SCs, melanocytes, and OECs. Rosa26 lineage tracing revealed that the Wnt1Cre2 mouse line recombines extensively in non-neural crest-derived tissues, while Sox10 Cre more selectively recombines in neural crest derivatives. We used Sox10 Cre mice to manipulate the Yap and Taz genes in migrating neural crest cells. Our analyses showed reduced Sox10+ cells in the nasal region and alterations in gene expression of SCs, melanocytes, and OECs. However, GnRH-1 neuronal migration remained unaffected. Notably, the loss of Yap and Taz in neural crest derivatives led to significant secondary effects in olfactory structures, reducing both olfactory sensory neurons and vascularization in the vomeronasal organ (VNO). Our findings highlight the importance of the Hippo pathway in OEC development and its implications for the olfactory vasculature. Whole embryonic noses were dissected from E14.5 yap flox/flox;taz flox/flox and Sox10cre;yap flox/WT;taz flox/flox mice, cells were isolated then analyzed using scRNAseq.嗅觉鞘细胞（Olfactory Ensheathing Cells, OECs）起源于神经嵴（neural crest），在介导嗅觉轴突束化并向脑部递送的过程中发挥关键作用。其发育对于促性腺激素释放激素-1（Gonadotropin-Releasing Hormone-1, GnRH-1）神经元的迁移至关重要，而这类神经元是维持青春期与生育能力的核心要素。尽管嗅觉鞘细胞的发育机制尚未完全阐明，但其在中枢神经系统损伤（central nervous system lesions）的潜在治疗中受到广泛关注。 我们对小鼠胚胎鼻组织开展的单细胞RNA测序（single-cell RNA sequencing, scRNAseq）分析显示，嗅觉鞘细胞与施万细胞（Schwann cells）共享源自施万细胞前体细胞（Schwann Cell Precursors, SCPs）的共同起源，但二者之间存在显著的遗传差异。 Wnt1在迁移前神经嵴细胞中呈高表达；而Sox10的表达则出现较晚，且在多数子代细胞中逐渐消失，仅在鼻软骨、施万细胞前体细胞、施万细胞、黑素细胞（melanocytes）及嗅觉鞘细胞中得以保留。 Rosa26谱系示踪（lineage tracing）实验显示，Wnt1Cre2小鼠品系可在非神经嵴来源组织中广泛发生基因重组，而Sox10-Cre则更具特异性地在神经嵴来源的子代细胞中实现重组。 我们利用Sox10-Cre小鼠，在迁移中的神经嵴细胞中对Yap与Taz基因进行了遗传操纵。分析结果显示，鼻部区域的Sox10阳性细胞数量减少，施万细胞、黑素细胞及嗅觉鞘细胞的基因表达谱亦发生改变，但促性腺激素释放激素-1神经元的迁移并未受到影响。 值得注意的是，神经嵴来源细胞中Yap与Taz的缺失，对嗅觉结构造成了显著的次生效应：犁鼻器（vomeronasal organ, VNO）内的嗅觉感觉神经元（olfactory sensory neurons）数量与血管形成（vascularization）水平均显著下降。 本研究结果凸显了Hippo通路在嗅觉鞘细胞发育中的关键作用，及其对嗅觉脉管系统的潜在调控意义。 实验中，我们从胚胎第14.5天的yap flox/flox;taz flox/flox纯合小鼠及Sox10cre;yap flox/WT;taz flox/flox小鼠中分离完整胚胎鼻部组织，获取细胞后通过单细胞RNA测序（scRNAseq）完成分析。