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Single celled organisms can change their behaviors in response to social signals. They can respond to changing environments and can differentiate from one cellular state to the another. Differentiation involves changes in which sets of genes are expressed, which polypeptides and proteins are made.
The ability of individuals to cooperate with one another, through processes such as quorum sensing, enables them to tune their responses so that they are appropriate and useful. Social interactions also makes it possible for them to produce behaviors that would be difficult or impossible for isolated individuals.
Once organisms learn, evolutionarily, how to cooperate, new opportunities and challenges (cheaters) emerge. There are strategies that can enable an organism to adapt to a wider range of environments, or to become highly specialized to a specific environment, through the production of increasingly complex behaviors.
Multicellularity can be transient – a pragmatic response to specific conditions, or it can be (if we ignore the short time that gametes exist as single cells) permanent, allowing the organism to develop the range of specialized cells types needed to build large, macroscopic organisms with complex and coordinated behaviors. In appears that various forms of multicellularity have arisen independently in a range of lineages.
Once organisms had developed quorum sensing, they can monitor the density of related organisms in their environment and turn or (or off) specific genes (or sets of genes, necessary to produce a specific behavior. While there are many variants, one model for such a behavior is a genetic toggle switch, in which a particular gene (or genes) can be switched on or off in response to environmental signals acting as allosteric regulators of transcription factor proteins.
One outcome of such a signaling system is to provoke the directional migration of amoeba and their aggregation to form the transient multicellular “slug”. Such behaviors has been observed in a range of normally unicellular organisms (see Hillmann et al., 2018)(↓). The classic example is the cellular slime 
mold Dictyostelium discoideum (Loomis, 2014). Under normal conditions, these unicellular amoeboid eukaryotes migrate, eating bacteria and such. In this state, the range of an individual’s movement is restricted to short distances.
However when conditions turn hostile, specifically a lack of necessary nitrogen compounds, there is a compelling reason to abandon one environment and migrate to another, more distant that a single-celled organism could reach. This is a behavior that depends upon the presence of a sufficient density (cells/unit volume) of cells that enables them to: 1) recognize one another’s presence (through quorum sensing), 2) find each other through directed (chemotactic) migration, and 3) form a multicellular slug that can go on to differentiate. Upon differentiation about 20% of the cells differentiate (and die), forming a stalk that lifts the other ~80% of the cells into the air. These non-stalk cells (the survivors) differentiate into spore (resistant to drying out) cells that are released into the air where they can be carried to new locations, establishing new populations.
The process of cellular differentiation in D. discoideum has been worked out in molecular detail and involves two distinct signaling systems: the secreted pre-starvation factor (PSF) protein and cyclic AMP (cAMP). PSF is a quorum signaling protein that also serves to activate the cell aggregation/differentiation program (FIG. ↓). If bacteria, that is food, are present, the activity of PSF is inhibited and cells remain in their single cell state. The key regulator of downstream aggregation and differentiation is the cAMP-dependent protein kinase PKA. In the unicellular state, PKA activity is inhibited by PufA. As PSF increases, while food levels decrease, YakA activity increases, inactivating PufA, leading to increased PKA activity. Active PKA induces the synthesis of two downstream proteins, adenylate cyclase (ACA) and the cAMP receptor (CAR1). ACA catalyzes cAMP synthesis, much of which is secreted from the cell as a signaling molecule. The membrane-bound CAR1 protein acts as a receptor for autocrine (on the cAMP secreting cell) and paracrine (on neighboring cells) signaling. The binding of cAMP to CAR1 leads to further activation of PKA, increasing cAMP synthesis and secretion – a positive feed-back loop. The result is a positive feedback loop; as cAMP levels increase, downstream genes are activated (and inhibited) leading cells to migrate toward one another, their adhesion to form a slug. Once the slug forms and migrates to an appropriate site, the process of differentiation (and death) leading to stalk and spore formation begins. The fates of the aggregated cells is determined stochastically, but social cheaters can arise.
Mutations can lead to individuals that avoid becoming stalk cells. In the long run, if all individuals were to become cheaters, it would be impossible to form a stalk, so the purpose of social cooperation would be impossible to achieve. In the face of environmental variation, populations invaded by cheaters are more likely to become extinct. For our purposes the various defenses against cheaters are best left to other courses (see here if interested Strassmann et al., 2000).
Clonal (permanent) multicellularity: The type of multicellularity that most developmental biology courses focus on is what is termed clonal multicellularity – the organism is a clone of an original cell, the zygote, a diploid cell produced by the fusion of sperm and egg, haploid cells formed through the process of meiosis (2). It is during meiosis that most basic genetic processes occur, that is the recombination between maternal and paternal chromosomes leading to the shuffling of alleles along a chromosome, and the independent segregation of chromosomes to form haploid gametes, gametes that are genetically distinct from those present in either parent. Once the zygote forms, subsequent cell divisions involve mitosis, with only a subset of differentiated cells, the cells of the germ line, capable of entering meiosis.
Non-germ line, that is somatic cells, grow and divide. They interact with one another directly and through various signaling processes to produce cells with distinct patterns of gene expression, and so differentiated behaviors. A key difference from a unicellular organism, is that the cells will (largely) stay attached to one another, or to extracellular matrix materials secreted by themselves and their neighbors. The result is ensembles of cells displaying different specializations and behaviors. As such cellular colonies get larger, they face a number of physical constraints – for example, cells are open non-equilibrium systems, to maintain themselves and to grow and reproduce, they need to import matter and energy from the external world. Cells also produce a range of, often toxic, waste products that need to be removed. As the cluster of zygote-derived cells grows larger, and includes more and more cells, some cells will become internal and so cut off from necessary resources. While diffusive processes are adequate when a cell is bathed in an aqueous solution, they are inadequate for a cell in the interior of a large cell aggregate (3). The limits of diffusive processes necessitate other strategies for resource delivery and waste removal; this includes the formation of tubular vascular systems (such as capillaries, arteries, veins) and contractile systems (hearts and such) to pump fluids through these vessels, as well as cells specialized to process and transport a range of nutrients (such as blood cells). As organisms get larger, their movements require contractile machines (muscle, cartilage, tendons, bones, etc) driving tails, fins, legs, wings, etc. The coordination of such motile systems involves neurons, ganglia, and brains. There is also a need to establish barriers between the insides of an organism and the outside world (skin, pulmonary, and gastrointestinal linings) and the need to protect the interior environment from invading pathogens (the immune system). The process of developing these various systems depends upon controlling patterns of cell growth, division, and specialization (consider the formation of an arm), as well as the controlled elimination of cells (apoptosis), important in morphogenesis (forming fingers from paddle-shaped appendages), the maturation of the immune system (eliminating cells that react against self), and the wiring up, and adaptation of the nervous system. Such changes are analogous to those involved in aggregative multicellularity.
Clonal (permanent) multicellularity: The type of multicellularity that most developmental biology courses focus on is what is termed clonal multicellularity – the organism is a clone of an original cell, the zygote, a diploid cell produced by the fusion of sperm and egg, haploid cells formed through the process of meiosis (2). It is during meiosis that most basic genetic processes occur, that is the recombination between maternal and paternal chromosomes leading to the shuffling of alleles along a chromosome, and the independent segregation of chromosomes to form haploid gametes, gametes that are genetically distinct from those present in either parent. Once the zygote forms, subsequent cell divisions involve mitosis, with only a subset of differentiated cells, the cells of the germ line, capable of entering meiosis.
Non-germ line, that is somatic cells, grow and divide. They interact with one another directly and through various signaling processes to produce cells with distinct patterns of gene expression, and so differentiated behaviors. A key difference from a unicellular organism, is that the cells will (largely) stay attached to one another, or to extracellular matrix materials secreted by themselves and their neighbors. The result is ensembles of cells displaying different specializations and behaviors. As such cellular colonies get larger, they face a number of physical constraints – for example, cells are open non-equilibrium systems, to maintain themselves and to grow and reproduce, they need to import matter and energy from the external world. Cells also produce a range of, often toxic, waste products that need to be removed. As the cluster of zygote-derived cells grows larger, and includes more and more cells, some cells will become internal and so cut off from necessary resources. While diffusive processes are adequate when a cell is bathed in an aqueous solution, they are inadequate for a cell in the interior of a large cell aggregate (3). The limits of diffusive processes necessitate other strategies for resource delivery and waste removal; this includes the formation of tubular vascular systems (such as capillaries, arteries, veins) and contractile systems (hearts and such) to pump fluids through these vessels, as well as cells specialized to process and transport a range of nutrients (such as blood cells). As organisms get larger, their movements require contractile machines (muscle, cartilage, tendons, bones, etc) driving tails, fins, legs, wings, etc. The coordination of such motile systems involves neurons, ganglia, and brains. There is also a need to establish barriers between the insides of an organism and the outside world (skin, pulmonary, and gastrointestinal linings) and the need to protect the interior environment from invading pathogens (the immune system). The process of developing these various systems depends upon controlling patterns of cell growth, division, and specialization (consider the formation of an arm), as well as the controlled elimination of cells (apoptosis), important in morphogenesis (forming fingers from paddle-shaped appendages), the maturation of the immune system (eliminating cells that react against self), and the wiring up, and adaptation of the nervous system. Such changes are analogous to those involved in aggregative multicellularity.
Unicellular affordances for multicellularity: When considering the design of a developmental biology course, we are faced with the diversity of living organisms – the basic observation that Darwin, Wallace, their progenitors and disciplinary descendants set out to solve. After all there are many millions of
different types of organisms; among the multicellular eukaryotes, there are six major group : the ascomycetes and basidiomycetes fungi, the florideophyte red algae, laminarialean brown algae, embryophytic land plants and animal.
and biotechnology). This approach is made possible by the discovery that the basic processes associated with animal (and metazoan) development are conserved. In this light, no observation has been more impactful than the discovery that the nature and organization of the genes involved in specifying the head to tail axes of the fruit fly and vertebrates (such as the mouse and human) is extremely similar in terms of genomic organization and function (Lappin et al., 2006 →), an observation that we will return to repeatedly. Such molecular similarities extend to cell-cell and cell-matrix adhesion systems, systems that release and respond to various signaling molecules, controlling cell behavior and gene expression, and reflects the evolutionary conservation and the common ancestry of all animals and King.
Early on in the history of comparative cellular anatomy, the striking structural similarities between the feeding system of choanoflagellate protozoans, a motile (microtubule-based) flagellum a surrounded by a “collar”of microfilament-based microvilli) and a structurally similar organelle in a range of multicellular organisms led to the suggestion that choanoflagellates and animals shared a common ancestor.
The advent of genomic sequencing and analysis has only strengthened this hypothesis, namely that choanoflagellates and animals form a unified evolutionary clade, the ‘Choanozoa’ (see tree↑ above)(Brunet and King, 2017). Moreover, “many genes required for animal multicellularity (e.g., tyrosine kinases, cadherins, integrins, and extracellular matrix domains) evolved before animal origins”. The implications is that the Choanozoan ancestor was predisposed to exploit some of the early opportunities offered by clonal multicellularity. These pre-existing affordances, together with newly arising genes and proteins (Long et al., 2013) were exploited in multiple lineages in the generation of multicellular organisms (see Knoll, 2011).
Basically to understand what happened next, some ~600 million years ago or so, we will approach the various processes involved in the shaping of animal development. Because all types of developmental processes, including the unicellular to colonial transition, involve changes in gene expression, we will begin with the factors involved in the regulation of gene expression.
Source: PLOS EveryONE