TNF&#x3b1;-dependent modulation of WT1-MMP9 regulatory axis links developmental and inflammatory pathways in glaucoma.

Tahseen Ahmed; Jyotishman Sarma; Meha Kabra; Shantanu Saha Roy; Samir Bera; Arun Kumar Mishra; Diganta Roy; Sayani Bagchi; Goutham Pyatla; Ashish Mishra; Sudipta Chakraborty; Anil K Mandal; Rohit C Khanna; Mahua Maulik; Subhabrata Chakrabarti; Moulinath Acharya

doi:10.1016/j.isci.2026.117176

PubMed · 42699107

TNFα-dependent modulation of WT1-MMP9 regulatory axis links developmental and inflammatory pathways in glaucoma.

Tahseen Ahmed·Jyotishman Sarma·Meha Kabra·Shantanu Saha Roy·Samir Bera·Arun Kumar Mishra·Diganta Roy·Sayani Bagchi·Goutham Pyatla·Ashish Mishra·Sudipta Chakraborty·Anil K Mandal·Rohit C Khanna·Mahua Maulik·Subhabrata Chakrabarti·Moulinath Acharya

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Abstract

Glaucomas are heterogeneous optic neuropathies associated with extracellular matrix dysregulation, abnormal ocular morphogenesis, and inflammatory signaling. Targeted deep sequencing of 586 primary congenital glaucoma (PCG) cases and 1,757 controls identified rare pathogenic variants in multiple genes, including WT1 and MMP9. Notably, WT1 variants clustered within the nuclear export sequence. Further, functional analyses showed that combined wt1-pax6 suppression in zebrafish disrupted ocular morphogenesis, highlighting developmental interdependence. In human trabecular meshwork cells, WT1 acted as a transcriptional repressor of MMP9, while TNF-α signaling triggered nitric oxide-dependent nuclear export of WT1, resulting in delayed MMP9 upregulation. This effect was reversible by inhibiting nuclear export or nitric oxide synthase. A patient-derived mutation in the nuclear-export region of WT1, disrupted this regulatory switch, causing abnormal MMP9 expression. These findings position WT1 as an important regulator linking developmental and inflammatory mechanisms in glaucoma pathogenesis.

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Tahseen Ahmed, Jyotishman Sarma, Meha Kabra, Shantanu Saha Roy, Samir Bera, Arun Kumar Mishra, Diganta Roy, Sayani Bagchi, Goutham Pyatla, Ashish Mishra, Sudipta Chakraborty, Anil K Mandal, Rohit C Khanna, Mahua Maulik, Subhabrata Chakrabarti, Moulinath Acharya. 2026-08-25. TNFα-dependent modulation of WT1-MMP9 regulatory axis links developmental and inflammatory pathways in glaucoma.. https://doi.org/10.1016/j.isci.2026.117176

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