# Understanding the role of the transcription factor Gli3 in Kallmann syndrome and normosmic forms of idiopathic hypogonadotropic hypogonadism.

> **NIH NIH R01** · STATE UNIVERSITY OF NEW YORK AT ALBANY · 2021 · $228,849

## Abstract

Summary
The GnRH-1 neurons are cells in the brain that control pubertal onset, sexual competence and fertility of
vertebrates. During development, the GnRH-1 neurons migrate from the embryonic nasal area into the brain,
where they will eventually take up positions in the hypothalamus to control the release of gonadotropins from the
pituitary gland. Defects in GnRH-1 migration induce various types of hypogonadotropic hypogonadism (HH) in
humans, characterized by delayed pubertal onset, hypogonadism, and infertility. HH in humans manifests
clinically as either Kallmann syndrome (KS) or normosmic idiopathic HH (nIHH). In KS, nIHH is associated with
deficiencies in the sense of smell. This association led to the long-held, prevailing view that the GnRH-1 neurons
migrate from the nose to the hypothalamus along the axons of olfactory and vomeronasal sensory neurons.
However, we still do not know whether his assumption of GnRH-1 migration patterns is true.
The overall objective of this application is to delineate the molecular mechanisms that guide GnRH-1 neurons
and their migratory scaffold. Our central hypothesis states that GnRH-1 neurons migrate to the hypothalamus
on the Terminal Nerve (TN), whose development occurs through molecular signals that only partially overlap
with those controlling olfactory and vomeronasal neuronal development. The rationale for this hypothesis derives
from understanding how specific genetic mutations linked to KS and nIHH can negatively affect TN development
and induce GnRH-1 neuron mispositioning, independent from the olfactory system development. Our preliminary
data indicate that transcriptional activator/repressor of the sonic hedgehog signaling pathway, Gli3, controls TN
developments and GnRH-1 migration to the brain. Guided by our strong preliminary data, we will test our
hypothesis through two specific aims: 1) Determine how the transcriptional regulator Gli3 regulates TN
development and GnRH-1 neuronal migration and 2) Define the biologic role of GLI3 mutations in the etiology of
KS/nIHH in humans. Our approach is innovative. We will exploit mouse genetics, advanced imaging techniques,
human whole genome sequencing data and complementary in-vitro and in-vivo experiments to discover new
mechanisms underlying TN development and formation of a functional GnRH-1 system in vertebrates. The
proposed research is significant, since it will advance and expand vital clinical information for KS and nIHH in
humans. The results from these studies will improve diagnostic criteria and stimulate the development of novel
treatments and therapeutic strategies to improve the human condition.

## Key facts

- **NIH application ID:** 10112936
- **Project number:** 5R01HD097331-03
- **Recipient organization:** STATE UNIVERSITY OF NEW YORK AT ALBANY
- **Principal Investigator:** Paolo E Forni
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $228,849
- **Award type:** 5
- **Project period:** 2019-03-12 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10112936

## Citation

> US National Institutes of Health, RePORTER application 10112936, Understanding the role of the transcription factor Gli3 in Kallmann syndrome and normosmic forms of idiopathic hypogonadotropic hypogonadism. (5R01HD097331-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10112936. Licensed CC0.

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