Tubulin Tyrosine Ligase–Like 1 Deficiency Results in Chronic Rhinosinusitis and Abnormal Development of Spermatid Flagella in Mice

Abstract

Tubulin tyrosine ligase-like 1 (TTLL1) protein is a member of the tubulin tyrosine ligase superfamily of proteins that are involved in the posttranslational polyglutamylation of tubulin in axonemal microtubules within cilia and flagella. To investigate the physiological role of TTLL1, the authors generated mice with a gene trap mutation in the Ttll1 gene that provide confirmation in a mammalian model that polyglutamylation plays an important role in some ciliary and flagellar functions. For the first time, mice homozygous for the Ttll1 mutation exhibited accumulations of exudates in the nasal passages and sinuses, rhinosinusitis, otitis media, and male infertility. In homozygous mutant male mice, abnormal sperm morphology and function were characterized by shortened or absent flagella and immotility. Although homozygous mutant males were infertile, the females were fertile. These findings are consistent with a diagnosis of primary ciliary dyskinesia (PCD) resulting from ciliary dysfunction. They indicate that Ttll1 is essential for normal motility of respiratory cilia and the biogenesis and function of sperm flagella but that the defect does not result in the hydrocephalus or laterality defects often seen in other forms of PCD. The absence of early-onset lethal hydrocephalus in Ttll1-mutant mice may enable studies to evaluate the long-term effects of PCD in the respiratory system of mice. Although no mutations in the orthologous gene have been linked with PCD in humans, investigating the role of TTLL1 and polyglutamylation of tubulin in cilia and flagella should advance an understanding of the biogenesis and function of these organelles in mammals and have potential diagnostic and therapeutic applications.

Post-translational modifications of microtubules

“…A morpholino-mediated depletion of the TTLL6 E-ligase in zebrafish is associated with shortening and loss of olfactory cilia (Pathak et al, 2007). In mice, mutations in either the TTLL1 E-ligase or associated protein PGs1 cause various defects in the sperm axoneme that are associated with male infertility (Campbell et al, 2002;Ikegami et al, 2010;Regnard et al, 2003;Vogel et al, 2010). Curiously, the Ttll1-deficient mice assemble structurally normal cilia in the trachea, despite low levels of tubulin glutamylation (but the motility of these cilia is strongly affected; see below) Vogel et al, 2010).…”

“…In mice, mutations in either the TTLL1 E-ligase or associated protein PGs1 cause various defects in the sperm axoneme that are associated with male infertility (Campbell et al, 2002;Ikegami et al, 2010;Regnard et al, 2003;Vogel et al, 2010). Curiously, the Ttll1-deficient mice assemble structurally normal cilia in the trachea, despite low levels of tubulin glutamylation (but the motility of these cilia is strongly affected; see below) Vogel et al, 2010). As discussed earlier for cytoplasmic microtubules, during axoneme assembly tubulin glutamylation can also act by regulating the microtubule-severing factors, specifically katanin.…”

Static respiratory cilia associated with mutations in Dnahc11/DNAH11: A mouse model of PCD

“…The Dnahc1 (MIM# 603332) null results in reduced tracheal cilia and sperm tail motility; however, no analysis of upper respiratory tract pathology was performed making it unclear how well this models PCD. A preliminary analysis of Ttll1 (MIM# 608955) mutants [Vogel et al, 2010] demonstrates PCD-like upper respiratory pathology, but ciliary motility and morphology has yet to be studied. These data led Ostrowski and colleagues to engineer postnatal deletion of Dnaic1 (MIM# 604366); deletion at 8-12 weeks of age avoids hydrocephalus.…”

Nucleoside diphosphate kinases (NDPKs) in animal development

“…All these data suggest that NME7 is involved in the biogenesis and function of motile cilia. Vogel and colleagues also reported that Nme5 -/-mice display a pathological phenotype highly suggestive of primary ciliary dyskinesia [107].…”

“…Constitutive Nme5 and Nme7 knockout mice were generated and described by Vogel and co-workers [96,107,108]. Nme7 knockout mice present defects like situs inversus (a congenital condition characterized by left-right transposition of thoracic and visceral organs and associated vasculature) and hydrocephalus [108] (Fig.…”