The secret life of IGSF1: from consternation to revelation
Bibliographic record
Abstract
Immunoglobulin superfamily, member 1 (IGSF1, formerly known as InhBP/p120) is a protein of unknown function, highly expressed in the pituitary gland. In this thesis, I characterized: 1) co- and post-translational processing of IGSF1, 2) expression of IGSF1 in several tissues, and 3) the link between IGSF1 and the hypothalamic-pituitary-thyroid (HPT) axis. The IGSF1/Igsf1 gene is located on the X chromosome, and multiple mRNA isoforms have been identified in both humans and mice. The canonical full-length protein is encoded by human mRNA isoforms IGSF1-1, IGSF1-3, and IGSF1-4, and murine Igsf1-1. Along with our collaborators, I demonstrated that the canonical full-length protein is co-translationally cleaved at an internal signal peptide into N-terminal (NTD) and C-terminal domains (CTD), and that N-linked glycosylation is important for trafficking of the CTD to the cell surface. I then investigated expression of IGSF1-CTD in the pituitary gland and several other tissues. Using a combination of approaches, I demonstrated Igsf1/IGSF1-CTD expression in anterior pituitary thyrotropes, somatotropes, and lactotropes, as well as in the murine hypothalamus and fetal liver. I also characterized the relative abundance of Igsf1 isoforms in the pituitary and hypothalamus, and the glycosylation patterns of IGSF1-CTD in different tissues.Finally, I sought to determine the function of IGSF1. Igsf1-deficient mice were previously generated by ablation of non-coding exon 1 (Igsf1Îex1). The mice were reported to be overtly normal, although analyses were largely limited to reproductive function, as IGSF1 had been predicted to play a role in the regulation of follicle-stimulating hormone synthesis. Our clinical collaborators identified mutations in IGSF1 in several male patients with central hypothyroidism. I showed that the disease-associated mutations lead to intracellular retention of the IGSF1-CTD protein, consistent with IGSF1 loss-of-function. Further, I analyzed HPT axis function of Igsf1-deficient male mice, and found that they phenocopy several features of the human disorder, thus confirming that loss of IGSF1 leads to central hypothyroidism. In addition, the mice have decreased pituitary thyroid-stimulating hormone (TSH) content and thyrotropin-releasing hormone receptor (Trhr) expression, suggestive of impaired TRH signaling. Overall, my work contributes to our understanding of IGSF1 expression, and describes a potential function for IGSF1 in regulating the HPT axis. Delineating molecular mechanisms of how IGSF1 acts in the pituitary gland to affect endocrine axes will contribute to the ongoing search for the function of this mysterious protein.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; both teacher heads agree on what is shown here.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".