Developmental biology - Cell Division Clock|
Timing Is Everything
Researchers describe genetic clockwork in germ cell development...
The nematode C. elegans is truly an organizational talent — the tiny animals, just one millimetre long, live for only two to three weeks with sexual maturity lasting only four days. Nevertheles, they manage to generate over 300 offspring during their brief life.
For this ambitious reproductive program to function optimally, a large number of processes must be synchronised within their cells. Geneticists at Martin Luther University Halle-Wittenberg (MLU) located in Saxony-Anhalt, Germany, have deciphered a central signalling pathway that encodes and controls these processes. Their study way recently published in the international scientific journal PNAS.
To reproduce, C. elegans must produce gametes — male spern and female eggs. These develop from undifferentiated (without a specific destiny) dividing stem cells. "Functional germ [sex] cells are special as they do not contain a double set of chromosomes, and thus are no longer capable of division," explains Christian R. Eckmann PhD, a developmental geneticist and Heisenberg Professor at MLU. Widely different programs have to be sequenced in parallel to produce gametes. "On one hand, genetic material of the source cells must be halved through cell division. On the other hand, sexual differentiation into male and female also has to take place. Extensive intracellular resturcturing is required to realize these processes, which have to mesh faultlessly if the cells are to develop successfully."
A highly intricate clockwork with many interlocking gears gives some idea of the level of sequencing complexity involved in forming gamete cells. Processes controlled by RNA-binding proteins.
Outside of the nucleus, in the cytoplasm, these proteins regulate the activation of selective genes. For a germ cell to develop from a stem cell, two specific RNA-binding proteins need to be destroyed before the cell's genetic program can reorganise.
How, when and why the signal for the developmental switch is given was previously unclear. Halle researchers have now figured out that the already familiar MAP kinase signalling pathway - a mitogen-activated protein that is specific to the amino acids serine and threonine - plays a central role.
"A protein degradation cascade is initiated via this [MAP kinase] molecular pathway, at the end of which two target proteins CPB-3 and GLD-1 are recognised, inactivated, and destroyed."
Christian R. Eckmann PhD, Developmental Geneticist, Institute of Biology, Martin Luther University Halle-Wittenberg, Germany.
Geneticists at MLU were able to demonstrate that this process already operates at a very early stage in meiosis (normal cell division) and corresponds temporally to the onset of sexual differentiation in female germ cells. "The special thing about these processes is they involve known molecules with very long evolutionary histories, previously receiving attention as suppressors of tumor formation within the context of normal cell division. In C. elegans, these molecules are interleaved in an innovative way. The processes were adapted and temporally co-ordinated to facilitate optimized, rapid germ cell production."
The findings of the MLU research group on Developmental Genetics suggest that the same genetic program may operate in germ cells of other, more complex organisms as well - albeit in a less compressed period of time.
The work reveals how Mitosis or normal cell cycle division generating two genetically identical sister cells, now differentiates into tissue-specific Meiotic germ cells (sex cells) through signals from the RNA-binding proteins CPB-3 and GLD-1.
RNA-binding proteins (RBPs) are key regulators of gene expression. Notably, germ cells deploy many distinct RBPs to guide their differentiation into haploid gametes. While the RNA-regulatory functions of RBPs are emerging, mechanisms controlling their activities and abundance are poorly understood. Due to its highly refined spatial organization, the gonad of Caenorhabditis elegans is an excellent model system to study temporal controls of RBP abundance. We used it to uncover a kinase-mediated protein-turnover axis that is built of evolutionarily conserved components, arranged in a unique manner, to couple RBP-target mRNA de-repression with RBP elimination at pachytene exit, a critical stage in early meiosis. This work reveals how meiotic cell cycle progression is coupled to tissue-specific differentiation events via signaling-induced RBP turnover.
RNA-binding proteins (RBPs) are important regulators of gene expression programs, especially during gametogenesis. How the abundance of particular RBPs is restricted to defined stages of meiosis remains largely elusive. Here, we report a molecular pathway that subjects two nonrelated but broadly evolutionarily conserved translational regulators (CPB-3/CPEB and GLD-1/STAR) to proteosomal degradation in Caenorhabditis elegans germ cells at the transition from pachytene to diplotene of meiotic prophase. Both RBPs are recognized by the same ubiquitin ligase complex, containing the molecular scaffold Cullin-1 and the tumor suppressor SEL-10/FBXW7 as its substrate recognition subunit. Destabilization of either RBP through this Skp, Cullin, F-box–containing complex (SCF) ubiquitin ligase appears to loosen its negative control over established target mRNAs, and presumably depends on a prior phosphorylation of CPB-3 and GLD-1 by MAPK (MPK-1), whose activity increases in mid- to late pachytene to promote meiotic progression and oocyte differentiation. Thus, we propose that the orchestrated degradation of RBPs via MAPK-signaling cascades during germ cell development may act to synchronize meiotic with sexual differentiation gene expression changes.
Edyta Kisielnicka, Ryuji Minasaki and Christian R. Eckmann.
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Nov 29, 2018 Fetal Timeline Maternal Timeline News News Archive
C. elegans, just one millimetre long, living for only two to three weeks - are extensively used in research - producing more than 300 offspring. Eggs (GREEN) being carried by the tiny worms.