Biology subjects

Melendez, A.

Publications and source records attributed to Melendez, A..

3 recordsLinked to original sources

bioRxiv2025

Astrocyte SEMA3C reduction improves Rett Syndrome phenotypes

Astrocytes support neuronal function during development through secreted proteins, yet how astrocyte-secreted cues are altered in disease states and contribute to neurodevelopmental disorders remains poorly defined. Rett syndrome (RTT) is a regressive neurodevelopmental disorder characterized by motor, sensory, and cognitive impairments. Here, we identify the class 3 semaphorin SEMA3C as an astrocyte-secreted protein that contributes to RTT pathology. We show that Sema3c expression is elevated in astrocytes in vivo in RTT model mice and find that SEMA3C is sufficient to inhibit cortical neuron dendrite outgrowth. Normalization of astrocyte SEMA3C levels in female RTT model mice rescues dendritic arborization deficits, restores synaptic activity, and improves visual acuity and motor behavior. Mechanistically, both SEMA3C and RTT astrocyte conditioned media inhibit dendrite outgrowth through PLXND1-dependent signaling. Together, these findings identify astrocyte-secreted SEMA3C as a contributor to RTT pathology and highlight SEMA3C and PLXND1 signaling as potential therapeutic targets in neurodevelopmental disorders.

neuroscience↗

bioRxiv2025

TBCK Deficiency Alters Ribosomal Function, RNA Splicing, and miRNA Networks: Insights from Multi-Omics Analyses

TBC1 domain-containing kinase (TBCK) is an important protein with implications in brain development. Biallelic variants in the TBCK gene are known to cause TBCK-related neurodevelopmental disorder (OMIM #616900) [1], a rare genetic multisystemic disease characterized by developmental delay, variable developmental regression, seizures, and premature death in late childhood for which no cure is currently available. Though previous work has provided a better understanding of the proteins role, the mechanism for how TBCK variants affect gene expression and protein regulation has remained understudied. To better understand the impact of these alterations, and using an unbiased approach, we employed the power of multi-omics to define the cellular consequences at the transcript and protein level. Our comprehensive analysis uncovered significant disruptions in ribosomal and translation-related pathways with widespread alternative splicing defects, and key miRNA changes that validate previously reported molecular findings. This work provides a clearer molecular framework for TBCK dysfunction in TBCK-/- cells and offers a valuable foundation to identify potential therapeutic targets.

genetics↗

bioRxiv2019

Mechanism of Interaction of BMP and Insulin Signaling in C. elegans Development and Homeostasis

A small number of peptide growth factor ligands are used repeatedly in development and homeostasis to drive programs of cell differentiation and function. Cells and tissues must integrate inputs from these diverse signals correctly, while failure to do so leads to pathology, reduced fitness, or death. Previous work using the nematode C. elegans identified an interaction between the bone morphogenetic protein (BMP) and insulin/IGF-1-like signaling (IIS) pathways in the regulation of lipid homeostasis. The molecular components required for this interaction, however, were not known. Here we report that INS-4, one of 40 insulin-like peptides (ILPs), is regulated by BMP signaling to modulate fat accumulation. Furthermore, we find that the IIS transcription factor DAF-16/FoxO, but not SKN-1/Nrf, acts downstream of BMP signaling in lipid homeostasis. Interestingly, BMP activity alters sensitivity of these two transcription factors to IIS-promoted cytoplasmic retention in opposite ways. Finally, we probe the extent of BMP and IIS interactions by testing two additional IIS functions, dauer formation and autophagy induction. Coupled with our previous work and that of other groups, we conclude that BMP and IIS pathways have at least three modes of interaction: independent, epistatic, and antagonistic. The molecular interactions we identify provide new insight into mechanisms of signaling crosstalk and potential therapeutic targets for IIS-related pathologies such as diabetes and metabolic syndrome.

cell biology↗