Most adult gonadotrophs originate from postnatal pituitary stem cells during minipuberty.

In the first three weeks postnatally, the pituitary gland undergoes a period of rapid growth, due to both cell proliferation and endocrine cell size increase. SCs are initially the most proliferative, and lineage tracing experiments previously showed that neonatal SCs can give rise to all endocrine cell types. However, because the Cre drivers used for lineage tracing were relatively inefficient and relied on tamoxifen, a selective estrogen receptor modulator which perturbs normal physiology, we could not decipher SC contribution to organ growth. We have thus performed lineage tracing using a new, more efficient and physiologically neutral Sox2rtTA allele. ­­When we traced early postnatal SCs using Sox2rtTA, we observed, similarly in both sexes, that most adult gonadotrophs derive from this neonatal SC population. These observations were confirmed and complemented by a single cell RNAseq dataset from postnatal day 3 (PND3) SOX9iresGFP XX and XY positive cells. From SOX9iresGFP cells, which comprise SCs and their immediate progeny, cell trajectories were inferred, and relevant gene regulatory networks predicted. Along with lineage tracing experiments, this dataset confirmed that SCs mostly differentiate into gonadotrophs postnatally. As animals develop, SC-derived gonadotrophs invade the gland, while the minor embryonic population remains confined ventrally. The discovery of a dual origin for gonadotrophs may help understand aspects of gonadotrophin regulation and mechanisms of diseases affecting puberty and fertility. FACsorted Sox9iresGFP positive cells from post-natal day 3 (PND3) males and females.

产后前三周，垂体腺（pituitary gland）会经历一段快速生长阶段，该过程由细胞增殖与内分泌细胞体积增大共同驱动。干细胞（stem cells, SCs）最初增殖活性最为旺盛，既往谱系示踪实验表明，新生期干细胞可分化为所有内分泌细胞类型。然而，由于既往谱系示踪所使用的Cre重组酶驱动系统效率相对较低，且依赖他莫昔芬（tamoxifen）——一种可干扰正常生理功能的选择性雌激素受体调节剂——因此我们无法阐明干细胞在器官生长中的贡献。为此，我们采用一种全新、高效且生理中性的Sox2rtTA等位基因开展谱系示踪实验。当我们通过Sox2rtTA标记示踪产后早期干细胞时，观察到两性均呈现一致结果：绝大多数成年促性腺激素细胞（gonadotrophs）均起源于该新生期干细胞群体。上述观察结果得到了产后第3天（postnatal day 3, PND3）SOX9iresGFP阳性XX、XY细胞的单细胞RNA测序（single cell RNA sequencing, scRNA-seq）数据集的验证与补充。针对包含干细胞及其直接子代细胞的SOX9iresGFP阳性细胞群，我们推断了细胞分化轨迹，并预测了相关基因调控网络。结合谱系示踪实验结果，该数据集证实产后干细胞主要分化为促性腺激素细胞。随着个体发育，干细胞来源的促性腺激素细胞会侵入垂体腺，而占比极少的胚胎起源促性腺激素细胞则始终局限于腹侧区域。此次发现促性腺激素细胞具有双重起源，或有助于阐明促性腺激素调控的相关机制，以及影响青春期发育与生育能力的疾病发病机制。本数据集的样本为产后第3天（PND3）雌雄小鼠的经荧光激活细胞分选（fluorescence-activated cell sorting, FACS）得到的SOX9iresGFP阳性细胞。