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. Overall design: FACsorted Sox9iresGFP positive cells from post-natal day 3 (PND3) males and females.