The IKC-leptin axis functions as a molecular bridge between neurodevelopment and endocrine signaling
Abstract
Kcnb1-null mice exhibit hypoleptinemia, disrupted Kcnb1-integrin-K⁺ channel complex (IKC) interactions with the leptin receptor (LepR) in proopiomelanocortin neurons, and broad neurodevelopmental and cognitive abnormalities. Because leptin is neurotrophic and IKC-LepR assemblies are present in neocortex, we tested whether leptin modifies these phenotypes. Early-life leptin supplementation partially improved behavioral and cognitive deficits and more strongly corrected anatomical and neuronal abnormalities. In null cortical neurons, leptin normalized dendritic overgrowth and F-actin dynamics through LepR- and integrin-dependent mechanisms. WT animals and neurons showed modest leptin responses; however, integrin manipulation unmasked leptin sensitivity, whereas LepR blockade induced null-like defects without exogenous leptin. These findings support a dual-mode model in which LepR signaling is regulated by both ligand availability and IKC-dependent mechanisms, identifying IKC-LepR coupling as a molecular interface linking endocrine signaling to neocortical development.
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BibTeX
@article{forzisi2026ikcleptin,
title = {{The IKC-leptin axis functions as a molecular bridge between neurodevelopment and endocrine signaling}},
author = {Elena Forzisi and Anika Gaur and Aniket Gaur and Maria del Carmen Medranda and Rachel Philip and Srishti Anand and Clotilde Impaloni and Kiarah Leonard and Srinidi Venkateswaran and Federico Sesti},
journal = {iScience},
year = {2026},
month = oct,
doi = {10.1016/j.isci.2026.117851},
url = {https://www.cell.com/iscience/fulltext/S2589-0042(26)03232-3},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - The IKC-leptin axis functions as a molecular bridge between neurodevelopment and endocrine signaling
AU - Elena Forzisi
AU - Anika Gaur
AU - Aniket Gaur
AU - Maria del Carmen Medranda
AU - Rachel Philip
AU - Srishti Anand
AU - Clotilde Impaloni
AU - Kiarah Leonard
AU - Srinidi Venkateswaran
AU - Federico Sesti
PY - 2026
DA - 2026/10/08
JO - iScience
DO - 10.1016/j.isci.2026.117851
UR - https://www.cell.com/iscience/fulltext/S2589-0042(26)03232-3
AB - Kcnb1-null mice exhibit hypoleptinemia, disrupted Kcnb1-integrin-K⁺ channel complex (IKC) interactions with the leptin receptor (LepR) in proopiomelanocortin neurons, and broad neurodevelopmental and cognitive abnormalities. Because leptin is neurotrophic and IKC-LepR assemblies are present in neocortex, we tested whether leptin modifies these phenotypes. Early-life leptin supplementation partially improved behavioral and cognitive deficits and more strongly corrected anatomical and neuronal abnormalities. In null cortical neurons, leptin normalized dendritic overgrowth and F-actin dynamics through LepR- and integrin-dependent mechanisms. WT animals and neurons showed modest leptin responses; however, integrin manipulation unmasked leptin sensitivity, whereas LepR blockade induced null-like defects without exogenous leptin. These findings support a dual-mode model in which LepR signaling is regulated by both ligand availability and IKC-dependent mechanisms, identifying IKC-LepR coupling as a molecular interface linking endocrine signaling to neocortical development.
SN - 2589-0042
ER -