Introduction
Dysfunction in primary cilia leads to a diverse group of disorders known as non-motile (primary) ciliopathies. These conditions exhibit significant clinical and genetic heterogeneity and are linked to nearly 200 genes. Among these genes, the tectonic (TCTN) family, comprised of TCTN1, TCTN2, and TCTN3, plays a pivotal role. These proteins are integral components of the ciliary transition zone and are crucial for proper ciliary function. Despite their importance, our understanding of the specific roles and mechanisms of TCTN proteins remains limited. This article aims to shed light on the structure, localization, and functions of TCTN proteins, their role in the Sonic Hedgehog (Shh) signaling pathway, and their involvement in primary ciliopathies.
Fig. 1 The protein interaction network of tectonic proteins. (Gong S., et al. 2018)
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Primary Cilia: Structure and Function
Cilium, a microtubule-based, antenna-like structure, originates from the basal body on the apical surface of cells during the G0/G1 phase. Under an electron microscope, a cilium can be divided into three parts: the basal body, the transition zone, and the axoneme. The basal body, formed by the transformation of the mother centriole, resides at the base of the cilia. It comprises nine circularly arranged triplets and distal appendages connecting with the cellular membrane.
The transition zone connects the distal end of the basal body to the proximal region of the axoneme using Y-linkers from axonemes to the ciliary membrane. The axoneme possesses nine peripheral doublets with or without two central singlets. Typically, motile cilia have a '9+2' microtubule pattern, including radial spokes, dynein arms, and nexin links, responsible for their mobility. In contrast, non-motile primary cilia usually have a '9+0' microtubule pattern, lacking the central microtubules and dynein arms.
Non-motile cilia, unlike their motile counterparts, do not facilitate movement but act as sensory organelles, playing a crucial role in signal transduction. They are integral to several developmental pathways, such as the Sonic Hedgehog (Shh), Wnt, fibroblast growth factor, platelet-derived growth factor receptor α, Notch, and Hippo pathways. Dysfunction in these pathways due to aberrant ciliary functions can lead to diverse ciliopathies.
Location and Structure of Tectonic Proteins
Tectonic family proteins, including TCTN1, TCTN2, and TCTN3, reside primarily in the transition zone of cilia. TCTN1 was the first identified member, recognized for its role in neural tube patterning through the Hedgehog pathway. Subsequent studies identified TCTN2 and TCTN3, adding to the complexity and significance of this protein family. Although all three TCTN proteins localize to the transition zone, TCTN2 and TCTN3 are also found in the cilium proper.
The human TCTN1 gene spans 35.4 kb on chromosome 12, encoding a protein with a yet unclear domain structure apart from an N-terminal signaling peptide. TCTN2, located on chromosome 12q24.31, encodes a 77-kDa protein featuring a signal peptide and a transmembrane domain. TCTN3 spans 30.7 kb on chromosome 10, completing the triad of tectonic proteins that regulate ciliary membrane composition and ciliogenesis in a tissue-dependent manner.
Functions of Tectonic Proteins
Regulation of Ciliary Membrane Composition
Tectonic proteins are essential in regulating the protein composition of the ciliary membrane. Some proteins, such as adenylyl cyclase 3 (AC3) and polycystic kidney disease 2 (PKD2), which are located in primary cilia, are lost or significantly reduced in Tctn1-, Tctn2-, or Tctn3-deficient mice or mutant mouse embryonic fibroblasts (MEFs). The absence of smoothened (Smo) and ADP-ribosylation factor-like protein 13B (Arl13b) in these mutants further emphasizes the crucial role of tectonic proteins in the successful transport of proteins into cilia.
Ciliogenesis
Tectonic proteins are also crucial for ciliogenesis in a tissue-dependent manner. Inactivating mutations of TCTN1, TCTN2, and TCTN3 in mice result in a significant reduction in the number of cilia in various tissues, indicating their fundamental role in ciliogenesis. Cilia are absent in the nodes and neural tubes of Tctn1- and Tctn2-deficient embryos, whereas atypical numbers of cilia appear in the notochord, early gut epithelium, and limb bud mesenchyme of Tctn1-deficient mice. Tctn3-deficient embryos show a significant reduction in cilia numbers in neural epithelia, mesencephalic vesicle, and notochord. This tissue-dependent ciliogenesis underscores the importance of tectonic proteins in the development of cilia.
Sonic Hedgehog (Shh) Pathway Regulation
Tectonic proteins are integral to the Shh signaling pathway. Mutations in these proteins result in developmental defects resembling those seen in disrupted Shh signaling. For instance, Tctn1 null mice exhibit phenotypes such as holoprosencephaly, microphthalmia, and limb polydactyly. These developmental issues correlate with changes in Shh pathway markers such as FoxA2, Nkx2.2, and Gli3 processing, reinforcing TCTN proteins' critical role in Shh pathway modulation.
Ciliopathies Associated with Tectonic Mutations
Non-motile ciliopathies are a group of diseases that arise due to primary cilium dysfunction leading to defects in signaling pathways. The mutations in tectonic genes TCTN1, TCTN2, and TCTN3 are associated with several ciliopathies, including Meckel-Gruber syndrome, Oral-facial-digital syndrome, and Joubert syndrome.
Meckel-Gruber Syndrome
Meckel-Gruber syndrome is a severe and rare autosomal recessive ciliopathy, first described by German anatomist Johann Friedrich Meckel in 1822. It features a classic triad of central nervous system malformation, polydactyly, and cystic renal diseases. Genetic mutations in various genes, including TCTN2, can cause Meckel-Gruber syndrome, emphasizing the role of tectonic proteins in mediating functional defects in cilia.
Oral-Facial-Digital Syndrome
Oral-Facial-Digital (OFD) syndrome is a group of heterogeneous disorders characterized by anomalies in the oral cavity, face, and digits. OFD syndrome is inherited mainly in an autosomal recessive pattern, except OFD type VIII, which is X-linked dominant. Causative genes for OFD syndrome include TCTN1 and TCTN3, highlighting the multiple roles of tectonic proteins during ciliogenesis.
Joubert Syndrome
Joubert syndrome is a rare autosomal recessive or X-linked recessive developmental disorder characterized by the presence of the molar tooth sign in magnetic resonance imaging. Genetic mutations in several genes, including TCTN1, TCTN2, and TCTN3, have been associated with Joubert syndrome. These mutations can disrupt the interactions of tectonic proteins with other proteins involved in umbrella molecular pathogenesis shared with other ciliopathies such as Meckel-Gruber syndrome.
Conclusion
In conclusion, tectonic proteins play multifaceted and indispensable roles in the proper functioning of primary cilia and the transduction of crucial developmental signals. Continued research into their specific functions, interactions, and mechanisms will pave the way for innovative therapeutic approaches, ultimately aiming to alleviate the burden of ciliopathies on affected individuals' lives.
References
- Gong S., et al. Tectonic proteins are important players in non-motile ciliopathies. Cellular Physiology and Biochemistry. 2018, 50 (1): 398-409.
- Wang C., et al. Three Tctn proteins are functionally conserved in the regulation of neural tube patterning and Gli3 processing but not ciliogenesis and Hedgehog signaling in the mouse. Developmental Biology. 2017, 430(1): 156-165.
- Thomas S., et al. TCTN3 mutations cause Mohr-Majewski syndrome. The American Journal of Human Genetics. 2012, 91(2): 372-378.
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