Defects in pituitary gland organogenesis are sometimes associated with congenital anomalies that affect head development. Lesions in transcription factors and signaling pathways explain some of these developmental syndromes. Basic research studies, including the characterization of genetically engineered mice, provide a mechanistic framework for understanding how mutations create the clinical characteristics observed in patients. Defects in BMP, WNT, Notch, and FGF signaling pathways affect induction and growth of the pituitary primordium and other organ systems partly by altering the balance between signaling pathways. The PITX and LHX transcription factor families influence pituitary and head development and are clinically relevant. A few later-acting transcription factors have pituitary-specific effects, including PROP1, POU1F1 (PIT1), and TPIT (TBX19), while others, such as NeuroD1 and NR5A1 (SF1), are syndromic, influencing development of other endocrine organs. We conducted a survey of genes transcribed in developing mouse pituitary to find candidates for cases of pituitary hormone deficiency of unknown etiology. We identified numerous transcription factors that are members of gene families with roles in syndromic or nonsyndromic pituitary hormone deficiency. This collection is a rich source for future basic and clinical studies.

Bone morphogenetic protein (Bmp) signaling is critical for the development and patterning of the mouse pituitary from the initial induction of Rathke's pouch to cell specification in the anterior lobe. We examined the regulation of Bmp signaling during pituitary development by analyzing null embryos for noggin, a Bmp 2 and 4 antagonist. Noggin is expressed in the ventral diencephalon during Rathke's pouch induction, in the underlying cartilage plate during cell specification and in the adult anterior pituitary gland. Noggin null embryos have a variable pituitary phenotype, which ranges from a rostrally displaced Rathke's pouch to induction of secondary pituitary tissue. While cell specification in the anterior pituitary appears normal, patterning in the ventral diencephalon is disrupted; Bmp4 activity is expanded resulting in Fibroblast growth factor 10 repression and in a rostral shift in the boundary between the Bmp4 and Sonic hedgehog expression domains. The expanded domain of Bmp4 activity also results in additional invaginations of oral ectoderm and can shift the position of Rathke's pouch or create secondary pituitary tissue. This work demonstrates the importance of attenuating the activity of Bmp signaling during pituitary induction in order to maintain the proper balance of signaling factors necessary for pituitary organogenesis.

The anterior and intermediate lobes of the pituitary gland are formed from Rathke's pouch. FGF, BMP and WNT signals emanating from the ventral diencephalon influence pouch growth and development. In order to examine the role of canonical WNT signaling during pituitary development we examined the pituitary expression of the TCF/LEF family of transcription factors, which mediate WNT signaling through the binding of beta-catenin. We report here the expression of several members of this family during pituitary development and the functional role of one member, TCF4 (TCF7L2), in the induction of the pituitary primordium. TCF4 is expressed in the ventral diencephalon early in pituitary development, rostral to a domain of BMP and FGF expression. Tcf4 deficient mice express Fgf10 and Bmp4; however, the Bmp and Fgf expression domains are expanded rostrally. As a result, additional pituitary progenitor cells are recruited into Rathke's pouch in Tcf4 mutants. Mutants also exhibit an expansion of the Six6 expression domain within Rathke's pouch, which may increase the number of proliferating pouch cells, resulting in a greatly enlarged anterior pituitary gland. This suggests that TCF4 negatively regulates pituitary growth through two mechanisms. The first mechanism is to restrict the domains of BMP and FGF signaling in the ventral diencephalon, and the second mechanism is the restriction of Six6 within Rathke's pouch. Thus, TCF4 is necessary both intrinsically and extrinsically to Rathke's pouch to ensure the proper growth of the pituitary gland.

RBX1 (RING box protein-1) or ROC1 (regulator of cullins-1) is the RING component of SCF (Skp1, Cullins, F-box proteins) E3 ubiquitin ligases, which regulate diverse cellular processes by targeting various substrates for degradation. However, the in vivo physiological function of RBX1 remains uncharacterized. Here, we show that a gene trap disruption of mouse Rbx1 causes embryonic lethality at embryonic day (E)7.5, mainly due to a failure in proliferation; p27, a cyclin dependent kinase inhibitor, normally undetectable in the early embryos, accumulates at high levels in the absence of Rbx1. Although mice heterozygous for the Rbx1 gene trap appear viable and fertile without obvious abnormalities, the Rbx1 ؉/Gt MEFs do show retarded growth with G1 arrest and p27 accumulation. Simultaneous loss of p27 extended the life span of Rbx1 Gt/Gt embryos from E6.5 to E9.5, indicating that p27-mediated cell cycle inhibition contributes to the early embryonic lethality in the Rbx1-deficient embryos. Our study demonstrates that the in vivo physiological function of RBX1 is to ensure cell proliferation by preventing p27 accumulation during the early stage of embryonic development.SCF E3 ubiquitin ligase ͉ protein degradation ͉ growth suppression

The intermediate and anterior lobes of the pituitary gland are derived from an invagination of oral ectoderm that forms Rathke’s pouch. During gestation proliferating cells are enriched around the pouch lumen, and they appear to delaminate as they exit the cell cycle and differentiate. During late mouse gestation and the post-natal period, anterior lobe progenitors re-enter the cell cycle and expand the populations of specialized, hormone-producing cells. At birth, all cell types are present, and their localization appears stratified based on cell type. We conducted a birth dating study of Rathke’s pouch derivatives to determine whether the location of specialized cells at birth is correlated with the timing of cell cycle exit. We find that all of the anterior lobe cell types initiate differentiation concurrently with a peak between e11.5 and e13.5. Differentiation of intermediate lobe melanotropes is delayed relative to anterior lobe cell types. We discovered that specialized cell types are not grouped together based on birth date and are dispersed throughout the anterior lobe. Thus, the apparent stratification of specialized cells at birth is not correlated with cell cycle exit. Thus, the currently popular model of cell specification, dependent upon timing of extrinsic, directional gradients of signaling molecules, needs revision. We propose that signals intrinsic to Rathke’s pouch are necessary for cell specification between e11.5 and e13.5 and that cell-cell communication likely plays an important role in regulating this process.