Biology subjects

Zouaghi, Y.

Publications and source records attributed to Zouaghi, Y..

3 recordsLinked to original sources

bioRxiv2026

Microglia Rank signaling regulates GnRH function and the Hypothalamic-Pituitary-Gonadal axis

The hypothalamic-pituitary-gonadal axis (HPG) controls pubertal development, sexual maturation, and fertility. We hereby demonstrate a new role of hypothalamic microglia in controlling the HPG axis through Rank signaling, a pathway known for its role in bone and mammary gland biology. Whole-body and microglia Rank depletion leads to hypogonadotropic hypogonadism (HH) resulting from an alteration in gonadotropin-releasing hormone (GnRH) function. In addition, we identify rare gene variants of RANK in patients with HH. Transcriptional profiling upon pubertal Rank loss reveals defective microglia activation and morphological alterations in the median eminence (ME), decreasing the contacts and engulfment of GnRH terminal projections and impairing GnRH responses to kisspeptin. Overall, our data uncovers the crucial role of microglia in regulating GnRH function through Rank signaling, with implications for reproductive maturation and fertility. One-Sentence SummaryMicroglia regulates GnRH function through RANK signaling

cell biology↗

bioRxiv2025

Deep learning the dynamic regulatory sequence code of cardiac organoid differentiation

Defining temporal gene regulatory programs driving human organogenesis is essential for understanding congenital defects. We combined a time-resolved, single-cell multi-omic atlas of human induced pluripotent stem cell-derived cardiac organoids with deep learning models of chromatin accessibility, enabling systematic discovery of cis-regulatory syntax underlying heart development and disease. This framework identified cell-state-specific motif syntax, linked motif instances to candidate target genes, and resolved programs governing lineage divergence. Integrating cell-state-resolved molecular profiles with computationally predicted variant effects from congenital heart disease (CHD) cases enabled the prioritization of noncoding variants predicted to disrupt developmental transitions, supporting the paradigm that disease etiology derives from perturbations to regulatory networks governing cardiogenesis. Experimental validation demonstrated that an intronic ANGPTL2 variant altered differentiation outcomes, implicating ANGPTL2 in CHD. This study bridges developmental regulation with disease genetics, establishing a framework for discovering the genetic and molecular basis of congenital disorders.

genetics↗

bioRxiv2023

Transcriptomic profiling of murine GnRH neurons reveals developmental trajectories linked to human reproduction

Gonadotropin-releasing hormone (GnRH) neurons play a crucial role in human reproduction and are associated with a spectrum of conditions. However, the underlying biological mechanisms remain elusive due to their small number and sparse distribution. We performed transcriptomic profiling of GnRH neurons during mouse embryonic development, revealing their molecular identity and gene expression dynamics. Our findings show that GnRH neurons undergo a profound transcriptional shift as they migrate from the nose to the brain and that distinct expression trajectories are associated with critical biological processes, including cell migration, neuronal projections, and synapse formation. Cell-to-cell communication analysis revealed timely and spatially restricted modulation of signaling pathways involving known molecules, such as Semaphorins and Plexins, and novel candidates, such as Neurexins and Endothelins. Using GWAS genes linked to human reproductive onset, we found a specific association with GnRH neuron trajectories rising in late developmental stages and involved in neuron maturation and connectivity. Finally, analysis of the genetic burden in a large cohort of patients with congenital GnRH deficiency revealed specific GnRH neuron trajectories with a significant mutation load compared to controls. In conclusion, this study revealed the gene expression dynamics underlying GnRH neuron embryonic development and provides novel insights linking GnRH neuron biology to human reproduction.

developmental biology↗