Ontogeny of anterior pituitary cell lineage

The embryonic development of the hypothalamo-pituitary complex has been primarily studied in rodents, using a combination of morphological, biochemical and genetic approaches. Information on the process of ontogeny has also benefitted from the availability of naturally occurring mutations and transgenic animal models. For an in-depth coverage of pituitary cell differentiation, the interested reader is referred to two reviews [29,43].

The ontogeny of the anterior pituitary depends upon a progressive cascade of activated extrinsic or intrinsic transcription factors and signaling molecules. The initial extrinsic phase of murine pituitary development comprises signals emanating from both the ventral diencephalon and the oral ectoderm. As illustrated in Figure 5.8A at mouse embryonic day (E) 6.5-7, the anterior portion of the neural plate is destined to give rise to the primordial pituitary, while the adjacent midline region will become the endocrine hypothalamus [43]. At E8, the oral ectoderm starts to proliferate in response to Shh, Six3, Otx2 and Hexl and participates in midline formation. Proliferation continues at E9 in response to Bmp4, Fgf8, Wnt2 and Nkx2 coming from the neural epithelium. At the same time, the oral ectoderm begins to invaginate upward and to form a rudimental Rathke's pouch, which expresses Lhx3/4 and Pitxl/2. At the edge of the pouch, Bmp2 makes contact with the oral ectoderm and antagonizes Fgf2, which is expressed by the neural epithelium. Subsequently, an Bmp2-Fgf8 ventral-dorsal gradient is established that determines the activation of specific genes in each cell group according to their localization within the pouch.

In parallel with the invagination of the oral ectoderm, pituitary precursor cells proliferate and migrate. The Wnt and Shh pathways regulate proliferation, while the Bmp and Fgf pathways participate in both proliferation and cellular migration. The formation of Rathke's pouch is complete at El0.5, and the pituitary precursor cells start expressing specific factors that determine their patterns of differentiation. Activation of distinct target genes occurs in response to an established dorsal-ventral gradient of Fgf8 and a ventral-dorsal gradient of Bmp2. Thus, depending on its location, each cell has a distinct starting point within the differentiation process (Figure 5.8A). For example, ventral cells express the transcription factors Isll and Gata2, while the dorsal cells express Pax6, Tpit and Propl.

Pituitary organogenesis in humans progresses along the same lines but at a different timescale (Table 5.2). It begins during week 4 of fetal development, when a thickening of cells in the oral ectoderm form the hypophysial placode, giving rise to Rathke's pouch. The pituitary organizer is a domain within the ventral diencephalon that expresses Bmp4, Fgf8, and Fgf 10, which induce the formation of the pituitary precursor, Rathke's pouch, from the oral ectoderm. The Wnt signaling pathway regulates this pituitary organizer such that loss of Wnt5a leads to an expansion of the pituitary organizer and

Ontogeny of the anterior pituitary in the mouse embryo

Figure 5.8 Ontogeny of the anterior pituitary in the mouse embryo. Panel A depicts the time course of development of the pituitary gland. Shown are the various transcription factors that affect the differentiation of the neural and/or oral ectoderm and their time of activation from day 6.5 to 10.5 of embryonic life.

E: embryonic day. See text for additional explanations. (Redrawn and modified from de Moraes, D.C. et al., J. Endocrinol.,

215, 239-245, 2012.) Panel В shows the pituitary-specific transcription factors involved in the development of the anterior pituitary from Rathke's pouch. Thyrotrophs, lactotrophs and somatotrophs are derived from a common lineage, determined by Prop-1 and Pit-1. Corticotrophs and gonadotrophs originate from independent lineages.

See text for other explanations. ACTH: adrenocorticotropic hormone; FSH: follicle-stimulating hormone; GH: growth hormone; LH: luteinizing hormone;

PRL: prolactin; TSH; thyroid stimulating hormone. (Redrawn and modified from Cohen, L.E. and Radovick, S„ Endocr.

Rev., 23, 431-442, 2002.)

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