Pituitary Development

The study of pituitary gland (hypophysis) development provides a remarkable example of cell specification. There are six major cell types of the anterior (endocrine) pituitary, and the fates of these cells are determined in a manner very similar to the ways in which the vertebrate neural tube is given its dorsal-ventral specificity and the Drosophila blastoderm is provided with anterior-posterior information. In other words, opposing gradients are converted into discrete domains of transcription factors, and these transcription factors specify the cell type of the tissue.

The cells destined to become the endocrine pituitary gland are located in the midline of the anterior neural ridge. The neural ridge is the extension of the neural folds, connecting the neural folds around the anterior portion of the embryo. It develops directly anterior to the ventral diencephalon. This midline neural ridge, in the roof of the pharynx, forms a pocket (Rathke's pouch) that comes into contact with, and invaginates into, the ventral diencephalon. Together they will form the pituitary, the anterior (endocrine) pituitary originating from Rathke's pouch, and the posterior (neural) pituitary originating from the ventral diencephalon. (Find more on human pituitary development.)

The six pituitary cell types of Rathke's pouch are the:

Thus, the cells of Rathke's pouch differentiate into some of the most important hormone secreting cells of the endocrine system. These cells emerge in a spatially specific fashion (Figure 1).

Figure 1
Figure 1   Cartoon showing Rathke's pouch primordium, wherein corticotropes (arising at embryonic day 12.5) are at the posterior tip; a population of rostral tip thyrocytes (also arising at day 12.5) are at the opposite corner. The most ventral cells are the gonadotropes, followed by the main thyrotropes, the somatotropes and lactotropes, and the melanotropes.

Scully and Rosenfeld (2002) have identified three major stages in the formation of the anterior pituitary gland: (1) extrinsic signals that cause cell proliferation and determination as pituitary; (2) intrinsic signaling gradients within Rathke's pouch activate a core group of transcription factors; and (3) commitment of cells to particular lineages through combinatorial associations of transcription factors.

Stage 1: Initial proliferation and induction.

The first stage of anterior pituitary growth and differentiation involves extrinsic paracrine signals from the diencephalon (dorsally) and from the pharyngeal (oral) ectoderm ventrolaterally (Figure 2). The diencephalon cells produce BMPs, Wnt5a, and FGF10. The oral ectoderm produces Sonic hedgehog. FGFs and sonic hedgehog are critically important at this stage. Knockouts of FGF10 or its receptor generate mice in which the Rathke's pouch cells fail to proliferate, undergoing apoptosis instead. BMP4 is required for the cell division of Rathke's pouch, and if BMP4 is inhibited or deleted at this time, no invagination of Rathke's pouch into the brain occurs. Sonic hedgehog is expressed throughout the oral ectoderm, except in the region that is destined to become Rathke's pouch (Kimura et al., 1996; Ericson et al., 1998; Treier et al., 1998). This combination of signals, from top and bottom, cause the Rathke's pouch cells to express the transcription factor Lhx3, a critical factor for specifying these cells as the precursors of the endocrine cell types (Sheng et al., 1997).

Figure 2
Figure 2   Extrinsic signals from diencephalon (FGFs, BMPs, Wnt5a) and the oral ectoderm (Shh) specify Rathke's pouch cells through the Lhx3 transcription factor. (After Scully and Rosenfeld, 2002).

Stage 2: Intrinsic signaling and specification.

The patterning of Rathke's pouch is established by intrinsic gradients of paracrine factors within the ectoderm, itself, and from the condensing mesenchyme associated with the pouch. First a ventral-to-dorsal gradient of BMP2 and Indian hedgehog is established within the ventral ectoderm of the pouch (BMP2) and in the condensing ventral mesenchyme (BMP2, Ihh). In the opposite direction is a dorsal-to- ventral gradient of FGFs. These gradients cause overlapping sets of transcription factors to be synthesized in different populations of cells, according to their positions along the dorsal-ventral axis (Figure 3). Many of these transcription factors are required to regulate the expansion of particular sets of multipotent precursor cells.

Figure 3
Figure 3   Intrinsic signals such as the ventral to dorsal gradient of BMP2 and the dorsal to ventral gradient of FGFs cause the production of different sets of transcription factors along the dorsal-ventreal axis of Rathke's pouch. (After Scully and Rosenfeld, 2002).

Stage 3. Cell commitment

The information in the transient gradients of paracrine factors becomes stabilized in the discrete pattern of transcription factor synthesis. This analogue-to-digital control mechanism is similar to that seen in the Drosophila blastoderm or the dorsal-ventral patterning of the vertebrate neural tube (Figure 4).

Figure 4
Figure 4   The opposing signaling gradients lead to cell specification along the dorsal-ventral axis. Different sets of transcription factors, each set induced by the strength of the different paracrine factors, direct the specification of the different cell types. (After Scully and Rosenfeld, 2002.)

Figure 5 shows the lineages of the anterior pituitary gland with respect to their transcription factors. At early stages, these cells are thought to be multipotent, but their fate becomes progressively limited by the sets of transcription factors contained within the nucleus. LHhx3-positive cells with no Prop-1 transcription factor become the rostral tip thyrocytes. Those cells acquiring transcription factor Tbx19 become the ventral corticotropes and the melanotropes, while the majority of pituitary cell types are derived from the cells that acquire the Prop-1 transcription factor.

Figure 5
Figure 5   Transcription factors and cell lineage compartments of the anetrior pituitary. The transcription factors are involved with the determination and differentiation of the particular cell types. (After Scully and Rosenfeld, 2002).

Of the Prop-1 positive cells, the ventral cells synthesize the GATA-2 transcription factor and make gonadotropes and thyrotropes. The dorsal cells of the Prop-1 lineage synthesize the PIT-1 transcription factor and generate the somatotropes, lactotropes, and also the thyrotropes. At high levels, PIT-1 inhibits the transcription of Gata-2, and GATA-2 inhibits the transcription of Pit-1. At lower levels of these factors, both can be synthesized (Dasen et al., 1999). When both Gata-2 and Pit-1 are activated, the PIT-1 protein can bind to its binding sites adjacent to Gata-2 sites and will activate the thyrotrope genes. Moreover, the PIT-1 protein will bind directly to the GATA-2 protein (with no DNA binding) and block its ability to activate the gonadotroph-specific genes.

The regulation of which Pit-1-positive cells become somatotrophs and which become lactotropes is very complicated. Multiple PIT-1 binding sites are involved in the genes producing growth hormone and prolactin, and the spacing between the PIT-1 binding sites of these genes may be critical in determining which hormone is made. It is possible that both cell types have the potential to make both hormones, but that cell-type-specific repressors are responsible for determining which genes become active. Moreover, the repression may be controlled by timing of whether activators or repressors bind first (see Daen et al., 2001).

The development of the pituitary gland is an excellent example of the specification of cell types by transient signaling gradients that induce sets of nuclear transcription factors. These transcription factors probably include both repressors and activators, and the enhancers on the genes integrate these signals to produce a transcriptional output.

References cited:

Dasen, J. S., and eight others. 1999. Reciprocal interactions of Pit1 and GATA2 mediate signaling gradient-induced determination of pituitary cell types. Cell 97: 587 — 598.

Dasen, S. J. and nine others. Temporal regulation of a paired-like homeodomain repressor/TLE corepressor complex and a related activator is required for pituitary organogenesis. Genes Dev. 15: 3193 — 3207.

Ericson, J., Norlin, S. Jessell, T. M., and Edlund, T. 1998. Integrated FGF and BMP signaling controls the progression of progenitor cell differentiation and the emergence of pattern in the embryonic anterior pituitary. Development 125: 1005 — 1015.

Kimura, S., Hara, Y., Pineau, T., Fernandez-Salguero, P., Fox, C. H., Ward, J. M,, and Gonzalez, F.J.1996. The T/ebp null mouse: thyroid-specific enhancer-binding protein is essential for the organogenesis of the thyroid, lung, ventral forebrain, and pituitary. Genes Dev. 10: 60 — 69.

Scully, K. M. and Rosenfeld, M. G. 2002. Pituitary development: Regulatory codes in mammalian organogenesis. Science 295: 2231 — 2235.

Sheng, H. Z., Moriyama, K., Yamashita, T., Li, H., Potter, S.S., Mahon, K.A., and Westphal, H. 1997. Multistep control of pituitary organogenesis. Science 278: 1809 — 1812.

Takuma N, and nine others. 1998. Formation of Rathke's pouch requires dual induction from the diencephalon. Development. 125: 4835 — 4840.

Treier, M., Gleiberman, A.S., O'Connell, S. M., Szeto, D.P., McMahon, J.A., McMahon, A.P., and Rosenfeld, M.G. 1998. Multistep signaling requirements for pituitary organogenesis in vivo Genes Dev. 12: 1691 — 1704.

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