Molecular mechanisms of pituitary organogenesis: In search of novel regulatory genes

Abstract

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 non-syndromic pituitary hormone deficiency. This collection is a rich source for future basic and clinical studies.

Figure 1. A guide for planning genetic screening for hypopituitary patients based on clinical findings

The patient characteristics identified by hormone screening, imaging studies, and analyses of syndromic features are itemized for each candidate gene based on currently known patient mutations. Note that for most genes there are variable hormone deficiencies, pituitary size and placement, and variable syndromic features.

Figure 2. LHX2 expression in the neural ectoderm

LHX2 immunoreactivity (green) is detected in sagittal sections of developing mice at e10.5 through e13.5. DAPI (blue) counterstain reveals nuclei of individual cells.

Figure 3. Tbx3 expression in the ventral diencephalon and prospective posterior lobe of the pituitary gland during development

Tbx3 transcripts are readily detectable in mid-sagittal sections of developing normal and Prop1^df/df mouse embryos at e12.5 and e14.5 by in situ hybridization.