Academic journal article Genetics

Modeling the Zebrafish Segmentation Clock's Gene Regulatory Network Constrained by Expression Data Suggests Evolutionary Transitions between Oscillating and Nonoscillating Transcription

Academic journal article Genetics

Modeling the Zebrafish Segmentation Clock's Gene Regulatory Network Constrained by Expression Data Suggests Evolutionary Transitions between Oscillating and Nonoscillating Transcription

Article excerpt

(ProQuest: ... denotes formulae omitted.)

SEGMENTATION of the anterior - posterior axis in verte- brate embryos results in the formation of somites, which are paired metameric structures within the paraxial meso- derm that lie on either side of the notochord and neural tube. Somites form sequentially, from anterior to posterior, during a process called somitogenesis. The precise temporal and spatial control of somitogenesis was first explained by the "clock and wavefront" model (Cooke and Zeeman 1976). This model proposes that segment formation results from the interaction of two distinct components: a posterior- progressing wavefront that coincides with axis elongation and genetic oscillations (the segmentation clock). Somite border formation occurs only when the wavefront encoun- ters cells in an appropriate phase of the clock. Thus, the clock gates wavefront activity, resulting in the creation of discrete, repeated tissue borders. The wavefront consists of Fgf and Wnt signals that originate in the tailbud, forming a posterior to anterior gradient that recedes as the tail elon- gates (Dubrulle et al. 2001; Sawada et al. 2001; Dubrulle and Pourquié 2004; Delfini et al. 2005; Aulehla et al. 2007; Naiche et al. 2011). The segmentation clock is composed of the hairy/enhancer of split-related (her/hes) family of Notch target genes (Palmeirim et al. 1997; Holley et al. 2000; Bessho et al. 2001). Components of the Fgf and Wnt signal- ing pathways oscillate in mouse and chick, suggesting a role for Fgf and Wnt in the clock, but the her/hes genes are the only conserved oscillatory clock components in mouse, chick, and zebrafish (Krol et al. 2011). The anole lizard and alligator segmentation clocks share some features with the zebrafish segmentation clock along with some character- istics found in the mouse or chick, suggesting that there is substantial variation in the segmentation clock network among vertebrate species (Eckalbar et al. 2012).

The her/hes genes form both hetero- and homodimers and negatively regulate their own transcription (Hirata et al. 2002; Holley et al. 2002; Oates and Ho 2002; Bessho et al. 2003; Gajewski et al. 2003; Giudicelli et al. 2007; Brend and Holley 2009a; Schröter et al. 2012; Trofka et al. 2012; Hanisch et al. 2013). Due to a short half-life, this negative feedback results in repeated cycles of expres- sion and repression of the her/hes genes within the preso- mitic mesoderm (PSM), the frequency of which correlates with the rate of somite formation (Lewis 2003; Monk 2003; Hirata et al. 2004; Ishii et al. 2008; Schröter and Oates 2010; Takashima et al. 2011; Delaune et al. 2012; Ay et al. 2013; Harima et al. 2013). Within the zebrafish seg- mentation clock, the repertoire of her/hes genes is ex- panded, and at least six members of the her/hes family play a role in clock oscillations-her1, her7, her11, her12, hes6, and her15 (Henry et al. 2002; Holley et al. 2002; Oates and Ho 2002; Kawamura et al. 2005; Sieger et al. 2004, 2006; Shankaran et al. 2007). We previously determined the dimerization partners of her1, her7, her11, her12, hes6, and her15. Between these six proteins, 10 dimers form in vivo, only 7 of which can strongly bind DNA. We identi- fied Hes6 as the hub of the protein dimer network, as it participates in half of the dimer species (Trofka et al. 2012). hes6 is also unique in that it is the only her/hes clock gene that does not oscillate during segmentation. Rather, hes6 forms a posterior-to-anterior gradient in the PSM that is promoted by Fgf signaling (Kawamura et al. 2005). How- ever, Hes6 protein levels do oscillate due to their heterodi- merization with the oscillating Her proteins (Schröter et al. 2012).

Loss-of-function studies suggest that the her genes have both unique and redundant functions within the clock. For example, although Her7 can bind DNA as a dimer with Hes6, Her7 primarily functions by modulating the topology of the dimer network by sequestering Hes6 and limiting the molecules available to dimerize with other Her proteins (Schröter et al. …

Search by... Author
Show... All Results Primary Sources Peer-reviewed

Oops!

An unknown error has occurred. Please click the button below to reload the page. If the problem persists, please try again in a little while.