The planar cell polarity (PCP) mutants of Drosophila show complex patterns of oriented bristles and hairs, as well as fine-scale mirror-image pattern reversals. Vertebrate PCP mutants show defects in embryonic convergent extension, cilia formation, neuronal pathfinding and left/right asymmetry; while PCP associated disease syndromes include myoclonus epilepsy, autism, neurodegeneration, deafness, polycystic kidney disease and cancer. The common factors are defective cytoskeletal organisation and signal transmission.
During cell division, the assembly of the mitotic spindle and cytoplasmic flux are driven by active transport mechanisms. Duplicated chromosomes separate along the mitotic spindle before contraction of an actin ring completes cell division. The control of these processes is so complex that individual genetic functions have become “entangled”. During early embryogenesis, cell shape and mitotic spindle orientation are precisely choreographed, with asymmetric partitioning of fate-determining factors. In Drosophila, the first divisions are syncytial in the centre of the egg, before nuclei migrate radially towards the cortical periplasm. This mechanism aligns mitotic spindles around the cortex of the egg, but with a random orientation in the embryonic surface plane. A few compact genes are transcribed, with polar mitotic waves travelling towards the equatorial midline. However, general activation of the zygotic genome is delayed until the cellular blastoderm stage, as individual nuclei become enclosed by membrane in-growth. The L/R flanks of the embryo are separated by a ventral furrow, with inward migration of flanking cells. During these cell shape changes, cortical actin fibrils are coupled, via trans-membrane linkages, to the extracellular matrix. Meanwhile, metachronal divisions spread across discrete mitotic domains, with spindles being aligned with respect to the embryonic axes. From this viewpoint, the cell-cycle progression both controls, and is regulated by, cytoskeletal remodelling. Transmembrane coupling may transmit mechanical stress between cells, followed by remodelling of the cortical periplasm, with cytoskeletal filaments extending throughout the cytoplasm. Thus, cytoskeletal remodelling is limited by strict topological constraints, while spindle assembly imposes a Cartesian axial system.
During germ band extension, the interstitial cells between the discrete mitotic domains divide asynchronously. These interstitial cells elongate along the anterior/posterior embryonic axis, as a chain of parasegmental twin-fields is delineated. In each cell, twin perinuclear centrioles migrate to the apical (Ap) cell surface, towards the end of G2, and become anchored to the cytoplasmic interface with the extracellular matrix. As the mitotic spindle is assembled, the separating matrix-anchored centrioles align cells with their neighbours and the extracellular matrix is displaced. In this context, the localisation of centrioles, Golgi and the nucleus is driven by motor protein assemblies; together with asymmetric partitioning of RNAs, proteins, vesicle cargos and lipid particles. Thus, active transport mechanisms have a critical function, in conjunction with the diffusion of intracellular morphogens. Active transport mechanisms remain essential throughout development, with proliferative growth being regulated via secreted morphogens. However, morphogen diffusion is limited by adsorption on the extracellular matrix, before uptake and transmission in the epithelial plane. Thus, the alignment of cytoplasmic interfaces may canalise morphogen flux between cells and the asymmetric partitioning of transcription factors (TFs).
The DNA duplex is wound around histone bobbins, with limited TF access. Within individual cells, global transcription patterns are differentially regulated, with altered euchromatic/heterochromatic boundaries. Chromatin compaction is dependent on the balance between Pc and Trx TFs, and co-ordinated via the Hox gene complexes. As the zygotic genome is activated, the release of paused PolII transcription complexes sets nucleosome phasing patterns. In consequence, supercoiled nucleosome chains extend across promoters, exons, introns and intragenic spacers. Thus, the sequential collapse of nucleosome bobbins may regulate PolII progression, spliceosome activity and the release of mature RNA transcripts. It follows that promoter architecture must co-evolve with regulatory segments and discrete chromatin insulator boundaries. The resultant genetic regulatory domains may overlap adjacent cognate transcripts and (otherwise) unrelated functions. In actively transcribed euchromatic segments, nucleosome phasing, may be set with respect to one, of the two, complimentary DNA strands. In principle, such nucleosome chains may re-assemble with alternative phasing following successive cell-cycle checkpoints, with differentially marked histones incorporated into nucleosome cores.
Within transcriptionally active domains, degenerate DNA binding sites may be occupied by weak-binding TFs with short residencies. Such transient interactions may be stabilised by specific co-factors, or competitively displaced, by different TFs with similar binding affinities. Thus, co-operative interactions across adjacent binding sites may drive non- linear binding kinetics. By contrast, strong-binding TFs, may be enhance, or restrain, progression of the PolII complex; while being less dependent on co-factor activity. In either case, the assembly, release, and degradation, of complex protein assemblies may modify individual TF activities; and the downstream metabolic functions that they regulate. Thus, integrated transcriptional, translational and post-translational networks control disparate morphogenetic responses. Alternative developmental pathways may be deployed in morphogenetic twin-fields, to either side of axes of mirror symmetry. However, individual cell fates remain labile until terminal PCP signalling, as the metabolic responses of adult cells are delimited. During terminal differentiation, the boundaries of actively transcribed chromatin domains may be re-set by asymmetric partitioning within rosette cell clusters. Thus, recursive, morphogenetic algorithms may allocate alternative fates to adjacent cells in differentiated tissues. In consequence, any limit to the information that may be encoded within the eukaryotic genome is indeterminate. The interactions between morphogenetic functions are hard to predict, while their mis-regulation results in a wide range of developmental defects and adult-onset diseases.
Initial Conjecture
During cytokinesis the organisation of the mother cell acts as a template to build twin daughter cells. The genome encodes sufficient information to replicate a pre-existing cell, but not its complete description. Morphogenetic mechanisms are dependent on extreme information compression, keyed to the cell-cycle oscillation.
PCP signalling - Index
© David Gubb, 2024
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