Topology and dynamics of the zebrafish segmentation clock core circuit.
During vertebrate embryogenesis, the rhythmic and sequential segmentation of the body axis is regulated by an oscillating genetic network termed the segmentation clock. We describe a new dynamic model for the core pace-making circuit of the zebrafish segmentation clock based on a systematic biochemical investigation of the network's topology and precise measurements of somitogenesis dynamics in novel genetic mutants. We show that the core pace-making circuit consists of two distinct negative feedback loops, one with Her1 homodimers and the other with Her7:Hes6 heterodimers, operating in parallel. To explain the observed single and double mutant phenotypes of her1, her7, and hes6 mutant embryos in our dynamic model, we postulate that the availability and effective stability of the dimers with DNA binding activity is controlled in a "dimer cloud" that contains all possible dimeric combinations between the three factors. This feature of our model predicts that Hes6 protein levels should oscillate despite constant hes6 mRNA production, which we confirm experimentally using novel Hes6 antibodies. The control of the circuit's dynamics by a population of dimers with and without DNA binding activity is a new principle for the segmentation clock and may be relevant to other biological clocks and transcriptional regulatory networks.
Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.
Christian
C
Schröter
Saúl
S
Ares
Luis G
LG
Morelli
Alina
A
Isakova
Korneel
K
Hens
Daniele
D
Soroldoni
Martin
M
Gajewski
Frank
F
Jülicher
Sebastian J
SJ
Maerkl
Bart
B
Deplancke
Andrew C
AC
Oates
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D001683:Biological Clocks / Q000235:genetics*; D019521:Body Patterning; D019281:Dimerization; D025461:Feedback, Physiological; D018507:Gene Expression Regulation, Developmental; D008954:Models, Biological; D010641:Phenotype; D011401:Promoter Regions, Genetic; D025941:Protein Interaction Mapping; D060066:Protein Interaction Maps; D055550:Protein Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D019170:Somites / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D013379:Substrate Specificity; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D020798:Two-Hybrid System Techniques; D015027:Zebrafish / Q000196:embryology / Q000235:genetics* / Q000378:metabolism; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
D051792:Basic Helix-Loop-Helix Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; D014157:Transcription Factors; D029961:Zebrafish Proteins; C460099:HER7 protein, zebrafish; C491619:her1 protein, zebrafish