Hypopituitarism occurs when the pituitary gland, a small, pea-sized gland at the base of the brain, does not make enough hormones that are essential for growth, metabolism, and reproduction. 

Lori Raetzman, a professor of molecular and integrative physiology in the School of Molecular & Cellular Biology, focuses much of her research on understanding pituitary gland development and related diseases like hypopituitarism. In recent years, she and members of her lab have been working to identify the genetic causes of hypopituitarism, leading her to study the growth hormone-releasing hormone receptor (GHRHR) gene. Mutations in this gene cause hypopituitarism in humans. 

"If we understood the pathway of how that's happening, we might be able to find a point at which we could intervene to help treat the disease," Raetzman said. 

Researchers have known that a loss-of-function mutation in the growth hormone-releasing hormone receptor gene would cause hypopituitarism. However, it was unclear how the mutation caused the disease to occur. To investigate the mechanism, researchers used mouse models with a loss-of-function mutation in GHRHR. Her team analyzed available single-cell RNA sequencing data of mouse pituitary samples, revealing a unique population of proliferating precursor cells expressing markers like POU1F1. 

POU1F1 is a transcription factor used as a marker to identify the transition from a stem cell to a differentiating cell in the research project. When a stem cell starts to make the intermediate proliferating cell before it becomes a mature growth hormone producing cell, that intermediate cell will turn on POU1F1 expression before expressing any other genes, Raetzman explained. The POU1F1 expression indicated the progenitor/precursor stage between stem cells and fully differentiated cells and helped the researchers characterize the unique proliferating precursor cell population they identified. 

To the surprise of researchers, in mice lacking GHRHR, this precursor cell population failed to expand properly, unlike the stem cells. Comparing the data with human single-cell data validated their findings. 

Their experiments and results were outlined in the article, “Characterization of Somatotrope Cell Expansion in Response to GHRH in the Neonatal Mouse Pituitary,” published in Endocrinology. 

The results "validate a long-held assumption about the way hormone pathways influence organ development,” said Richard Gonigam (BS, molecular and cellular biology, ’19), a former undergraduate researcher in the Raetzman lab.

Undergraduate organized experiments, optimized techniques 
Gonigam joined Raetzman’s lab in 2016 as an undergraduate student and performed some of the research as a recipient of a School of MCB Summer Undergraduate Research Fellowship. Initially, he joined the lab out of curiosity; he had no idea his research project would lead to primary authorship on a published study, he said. 

At first, he assisted research scientist Karen Weis with mice breeding, but as his interest grew, he soon took on ownership of the project under Dr. Raetzman's guidance. Gonigam demonstrated a high level of scientific thinking that proved instrumental to the success of the research, Raetzman said. He dedicated long hours over multiple years, driven by his curiosity to understand the science. As an undergraduate researcher, he organized experiments, optimized techniques, identified and interpreted findings from the data that advanced the project's goals, and proposed next steps.  

The experience revealed his passion for research and cultivated valuable scientific skills, preparing him for a future career in applying scientific knowledge. Today, he is a medical technologist at UChicago Medicine. 

Through single-cell RNA sequencing of mouse models with and without functional GHRHR, Dr. Raetzman's lab identified a unique proliferating precursor cell population critical for proper pituitary development. In the future, she and members of her lab will continue their work in further understanding hypopituitarism in hopes of laying the groundwork for potential new treatment approaches. 

Upon reflection of their work, Gonigam said it provided foundational, basic science research that proves what scientists have assumed for the last 40 years.  

“It was a fair assumption, but it's good to still do the basic research and have a model and data to support that assumption. Having that evidence provides a basis to move on to the next step. You can’t do the next study, starting to elucidate a fix for a disease state, without absolutely having evidence for all the basic assumptions you’re working with,” he said. 

This work was supported by the National Institutes of Health.