2020/06/22

LUZP1, a novel regulator of primary cilia and the actin cytoskeleton, is a contributing factor in Townes-Brocks Syndrome

Townes-Brocks Syndrome (TBS) is caused by dominant mutations in the gene SALL1, leading to a broad spectrum of symptoms including frequent renal and heart impairment. Recent work from Barrio’s Laboratory has shown that cells from TBS patients exhibit cilia defects, perhaps due to dominant interference by mutant SALL1 on factors that influence cilia function. Most animal cells are able to display antenna-like structures called primary cilia on their surface that help them to sense their surroundings. Primary cilia are assembled from protein filaments and regulatory complexes at a certain phase of the cell division cycle. Cilia assembly is influenced by multiple cellular systems, including the actin cytoskeleton. Cilia defects can cause or contribute to many human diseases, collectively termed “ciliopathies”.

In the present publication, Bozal-Basterra and colleagues built upon their previous work and characterize LUZP1, a regulator of cilia assembly and the actin cytoskeleton. Loss of LUZP1 in mouse fibroblasts leads to increased cilia length and numbers, with defects in the cilia-based Sonic hedgehog signaling pathway. These cells also have a weakened actin cytoskeleton, likely due to defective bundling of actin filaments. TBS patient-derived fibroblasts have reduced LUZP1 levels and exhibited similar cilia and cytoskeletal defects, suggesting that LUZP1 dysfunction may partially underlie TBS etiology.

The work was leaded by Barrio’s Lab at CIC bioGUNE and was done in collaboration with an international team of researchers from USA (Stanford University, Stanford, California, Massachusetts Institute of Technology, Cambridge, Massachusetts), and researchers at the University of the Basque Country (the Department of Genetics, Physical Anthropology and Animal Physiology, the Achucarro Basque Center for Neuroscience, and the Analytical & High Resolution Biomedical Microscopy Core Facility). These results are published by the prestigious journal eLife.

These findings shed light on the cross-talk of primary cilia and actin cytoskeleton, and provide new insight into the mechanisms underlying TBS, a rare disease for which no treatment currently exists. Further work is necessary to define how mutant SALL1 acts upon LUZP1 stability and other cilia regulatory factors. TBS has an estimated incidence of less than 1 in 350000 new-borns. The research on TBS could have an impact on the on the interpretation of other syndromes linked to SALL factors.

Figure Caption: Till division do us part Immunofluorescence micrographs showing LUZP1 in the cytoplasm of two dividing cells (green) and in the midbody (yellow), an actin structure formed during cell division. Microtubules are shown in red and nuclei in blue.

Reference: Bozal-Basterra L, Gonzalez-Santamarta M, Muratore V, Bermejo-Arteagabeitia A, Da Fonseca C, Barroso-Gomila O, Azkargorta M, Iloro I, Pampliega O, Andrade R, Martín-Martín N, Branon TC, Ting AY, Rodríguez JA, Carracedo A, Elortza F, Sutherland JD*, Barrio R*. LUZP1, a novel regulator of primary cilia and the actin cytoskeleton, is a contributing factor in Townes-Brocks Syndrome. eLife 2020;9:e55957 doi: 10.7554/eLife.55957