Sheridan, Daniel; (2024) Determination of the SOX2 stem cell contribution to the formation of new endocrine cells in the postnatal murine pituitary. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The murine pituitary gland undergoes rapid expansion during the first 3 weeks of life postnatally. The precise dynamics of this expansion and the underlying processes, including the role of SOX2-expressing pituitary stem cells (PSCs), are not yet fully understood. Utilising single-cell RNA sequencing (scRNAseq), lineage tracing, and genetic, surgical and pharmacological manipulation of endocrine axes, the investigations performed for this project provide novel insights into PSC function postnatally. First, the dynamics of developing endocrine cell type populations were followed from birth up to 1 year of age in both sexes. The rapid pituitary cell expansion observed during the first three weeks of life is shown to be driven only partly by the proliferation of differentiated endocrine cells, primarily due to somatotroph and lactotroph expansion. While SOX2+ PSC progeny were identified to contribute to approximately 10% or less of most endocrine cell types, PSCs give rise to the majority (>70%) of the adult gonadotroph population, becoming largely established by the time of minipuberty. WNT signalling is likely to be important for this postnatal differentiation because the downstream effector LEF1 is transiently upregulated as cells commit. Lef1CreERT2/+ lineage tracing confirmed this observation, revealing that LEF1+ progeny contributed in low numbers to postnatal gonadotrophs alongside all endocrine cell types, as observed in SOX2 lineage tracing analyses. While gonadotrophs are regulated by both hypothalamic and gonadal signals, postnatal gonadotroph differentiation occurs independently of these, because normal differentiation occurs following pharmacological androgen or gonadotropin-releasing hormone receptor inhibition, or gonadectomy. Putative regulatory factors and signalling pathways were identified, including LEF1, NEUROD1, HEDGEHOG and WNT signalling. However, no impact on gonadotroph emergence was seen in mice mutant for genes encoding these individual factors, demonstrating a more complex regulatory process.

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