Compensatory growth renders Tcf7l1a dispensable for eye formation despite its requirement in eye field specification
ELIFE
Authors: Young, Rodrigo M.; Hawkins, Thomas A.; Cavodeassi, Florencia; Stickney, Heather L.; Schwarz, Quenten; Lawrence, Lisa M.; Wierzbicki, Claudia; Cheng, Bowie Y. L.; Luo, Jingyuan; Ambrosio, Elizabeth Mayela; Klosner, Allison; Sealy, Ian M.; Rowell, Jasmine; Trivedi, Chintan A.; Bianco, Isaac H.; Allende, Miguel L.; Busch-Nentwich, Elisabeth M.; Gestri, Gaia; Wilson, Stephen W.
Abstract
The vertebrate eye originates from the eye field, a domain of cells specified by a small number of transcription factors. In this study, we show that Tcf7l1a is one such transcription factor that acts cell-autonomously to specify the eye field in zebrafish. Despite the much-reduced eye field in tcf7l1a mutants, these fish develop normal eyes revealing a striking ability of the eye to recover from a severe early phenotype. This robustness is not mediated through genetic compensation at neural plate stage; instead, the smaller optic vesicle of tcf7l1a mutants shows delayed neurogenesis and continues to grow until it achieves approximately normal size. Although the developing eye is robust to the lack of Tcf7l1a function, it is sensitised to the effects of additional mutations. In support of this, a forward genetic screen identified mutations in hesx1, cct5 and gdf6a, which give synthetically enhanced eye specification or growth phenotypes when in combination with the tcf7l1a mutation.
Structure of the human TRiC/CCT Subunit 5 associated with hereditary sensory neuropathy
SCIENTIFIC REPORTS
Authors: Pereira, Jose H.; McAndrew, Ryan P.; Sergeeva, Oksana A.; Ralston, Corie Y.; King, Jonathan A.; Adams, Paul D.
Abstract
The human chaperonin TRiC consists of eight non-identical subunits, and its protein-folding activity is critical for cellular health. Misfolded proteins are associated with many human diseases, such as amyloid diseases, cancer, and neuropathies, making TRiC a potential therapeutic target. A detailed structural understanding of its ATP-dependent folding mechanism and substrate recognition is therefore of great importance. Of particular health-related interest is the mutation Histidine 147 to Arginine (H147R) in human TRiC subunit 5 (CCT5), which has been associated with hereditary sensory neuropathy. In this paper, we describe the crystal structures of CCT5 and the CCT5-H147R mutant, which provide important structural information for this vital protein-folding machine in humans. This first X-ray crystallographic study of a single human CCT subunit in the context of a hexadecameric complex can be expanded in the future to the other 7 subunits that form the TRiC complex.
COA
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