On the evolution of development

Abstract

Perhaps development is more than just morphogenesis. We now recognize that the conceptus expresses epigenetic marks that heritably affect it phenotypically, indicating that the offspring are to some degree genetically autonomous, and that ontogeny and phylogeny may coordinately determine the fate of such marks. This scenario mechanistically links ecology, ontogeny and phylogeny together as an integrated mechanism for evolution for the first time. As a functional example, the Parathyroid Hormone-related Protein (PTHrP) signaling duplicated during the Phanerozoic water-land transition. The PTHrP signaling pathway was critical for the evolution of the skeleton, skin barrier, and lung function, based on experimental evidence, inferring that physiologic stress can profoundly affect adaptation through internal selection, giving seminal insights to how and why vertebrates were able to evolve from water to land. By viewing evolution from its inception in unicellular organisms, driven by competition between pro- and eukaryotes, the emergence of complex biologic traits from the unicellular cell membrane offers a novel way of thinking about the process of evolution from its beginnings, rather than from its consequences as is traditionally done. And by focusing on the epistatic balancing mechanisms for calcium and lipid homeostasis, the evolution of unicellular organisms, driven by competition between pro- and eukaryotes, gave rise to the emergence of complex biologic traits derived from the unicellular plasma lemma, offering a unique way of thinking about the process of evolution. By exploiting the cellular-molecular mechanisms of lung evolution as ontogeny and phylogeny, the sequence of events for the evolution of the skin, kidney and skeleton become more transparent. This novel approach to the evolution question offers equally novel insights to the primacy of the unicellular state, hologenomics and even a priori bioethical decisions.

Keywords: Parathyroid Hormone-related Protein; cell-cell signaling; evolution; growth factor signaling; homeostasis; homology; ontogeny; paracrine; phylogeny; unicellular state.

Fig. 1

Lung biologic continuum from ontogeny–phylogeny to homeostasis and repair. The schematic compares the cellular– molecular progression of lung evolution from the fish swim bladder to the mammalian lung (left portion) with the development of the mammalian lung, or evo-devo, as the alveoli become progressively smaller (see legend in upper left corner), increasing the surface area-blood volume ratio. This is facilitated by the decrease in alveolar myofibroblasts, and the increase in lipofibroblasts, due to the decrease in Wingless/int (Wnt) signaling, and increase in PTHrP signaling, respectively. Lung fibrosis progresses in the reverse direction (lower left corner). Lung homeostasis (right portion) is characterized by PTHrP/leptin signaling between the type II cell and lipofibroblast, coordinately regulating the stretch regulation of surfactant production with alveolar capillary perfusion- PTHrP acts as both a potent vasodilator and stimulates lipofibroblast uptake of the surfactant phospholipid substrate triglyceride (TG), which is actively transferred to the type II cell for surfactant synthesis. Failure of PTHrP signaling causes increased Wnt signaling, decreased PPARγ expression by lipofibroblasts, and transdifferentiation to myofibroblasts, causing lung fibrosis. Repair (arrow from homeostasis back to ontogeny–phylogeny), is the recapitulation of ontogeny–phylogeny, resulting in increased PPARγ expression.

Figure 2. The alveolus and glomerulus are stretch sensors

In the lung (left panel), the alveolar epithelium (square) and fibroblast (oval) respond to the stretching of the alveolar wall by increasing surfactant production. In the kidney (right panel), the mesangium (oval) senses fluid pressure and regulates bloodflow in the glomeruli. In both cases, breakdown in cell–cell interactions causes these cells to become fibrotic (brown cell) due to upregulation of Wnt.

Fig. 3

Alternating extrinsic and intrinsic selection pressures for the genes of lung phylogeny and ontogeny. The effects of the extrinsic factors (salinity, land nutrients, and oxygen on the x-axis) on genes that determine the phylogeny and ontogeny of the mammalian lung alternate sequentially with the intrinsic genetic factors (y-axis), highlighted by the squares and circles, respectively. Steps 1–11 appear in the sequence they appear during phylogeny and ontogeny: [1] AMPs; [2] VDR; [3] type IV collagen; [4] GR; [5] 11β HSD; [6] βAR; [7] ADRP; [8] leptin; [9] leptin receptor; [10] PTHrP; and [11] SP-B. Steps 12–17 represent the pleiotropic effects of leptin on the EGF in oval signaling pathways integrating steps 1–6, 10, and 11. Steps 18–20 are major geologic epochs that have “driven” intrinsic lung evolution.