Evolving gene regulatory networks into cellular networks guiding adaptive behavior: an outline how single cells could have evolved into a centralized neurosensory system

Abstract

Understanding the evolution of the neurosensory system of man, able to reflect on its own origin, is one of the major goals of comparative neurobiology. Details of the origin of neurosensory cells, their aggregation into central nervous systems and associated sensory organs and their localized patterning leading to remarkably different cell types aggregated into variably sized parts of the central nervous system have begun to emerge. Insights at the cellular and molecular level have begun to shed some light on the evolution of neurosensory cells, partially covered in this review. Molecular evidence suggests that high mobility group (HMG) proteins of pre-metazoans evolved into the definitive Sox [SRY (sex determining region Y)-box] genes used for neurosensory precursor specification in metazoans. Likewise, pre-metazoan basic helix-loop-helix (bHLH) genes evolved in metazoans into the group A bHLH genes dedicated to neurosensory differentiation in bilaterians. Available evidence suggests that the Sox and bHLH genes evolved a cross-regulatory network able to synchronize expansion of precursor populations and their subsequent differentiation into novel parts of the brain or sensory organs. Molecular evidence suggests metazoans evolved patterning gene networks early, which were not dedicated to neuronal development. Only later in evolution were these patterning gene networks tied into the increasing complexity of diffusible factors, many of which were already present in pre-metazoans, to drive local patterning events. It appears that the evolving molecular basis of neurosensory cell development may have led, in interaction with differentially expressed patterning genes, to local network modifications guiding unique specializations of neurosensory cells into sensory organs and various areas of the central nervous system.

Fig. 1

This figure displays the relationship of single-celled and multicellular organisms and some critical events concerning the evolution of neurons and sensory systems. 1) Complicated life cycle with transient multicellularity; 2) most cellular communication signals are present, of Sox like and bHLH genes are present 3) class A bHLH genes and SoxB genes that can induce neurons are present. 4) epithelial nerve nets and sensory organs evolve; 5) miR-124 specific for neurons and miR-183 specific for sensory cells appear; 6) ventral central nervous system evolves; 7) ‘skin brains’ with chordate like patterning evolve; 8) neurons are concentrated in a dorsal neural tube and composite, organ like sensory cell groups appear. 9) Vertebrate sensory organs and nervous system appear. # note that the position of Ctenophora is disputed. *Acoela are sometimes combined with Xenoturbella, indicating perhaps limited molecular distinction between basic bilaterians and basic deuterostomes. Compiled after (Gyoja, 2014, Osigus, et al., 2013, Peterson, et al., 2013, Schnitzler, et al., 2014, Suga, et al., 2013, Swalla and Smith, 2008)

Fig. 2

Available data on basic helix-loop-helix transcription factors (bHLH TFs) relevant for the evolution of human hair cells and sensory neurons are shown. Note that Monosiga has 11 bHLH TFs, none of which are orthologous to Metazoans. Eumetazoans have sensory cells with axons and display asymmetric distribution of microvilli (yellow) and kinocilium (gray). In mammals, the three bHLH TFs are partially overlapping to drive neuronal (Neurog1, Neurod1) and hair cell (Atoh1, Neurod1) development. A superficially similar arrangement of sensory cells and sensory neurons is found in some mollusks but which bHLH genes are expressed in these cells is unknown. Given the distribution in protostomes and deuterostomes, mollusk and vertebrates sensory cell evolution without an axon likely indicates functional conservation. Modified after (Pan, et al., 2012).

Fig. 3. The interactions of Sox and bHLH genes in neurosensory differentiation of a mouse

Experimental data in mice have shown a complex interaction of Sox genes and bHLH genes in the progression of neurosensory cell fate commitment and differentiation. a) Sox2 and Sox9 are essential genes in neurosensory precursor cells that ensure self-renewal of precursors but also commitment to the neurosensory lineage. This appears to be in interaction with several bHLH genes that are later found in astrocytes (Hes, Hey, Id). Virtually all of these neurosensory precursor genes are turned off in the neurosensory lineage (arrow with – on transition) and mostly bHLH genes are activated, including Sox21 that antagonizes Sox2. Oligodendrocyte precursors also shut off neurosensory precursor genes but are characterized by a different set of bHLH genes (Olig1/2) and Sox10 and Sox2 for terminal differentiation. bHLH transcription factors can form complex interactions in a given cell that can undergo periodic changes (oscillates) and their signal can undergo context dependent variation between gene expression and suppression. Data in mice and flies suggest that all proneural transcription factors compete for the E-proteins (Tcf3,4,12) to form heterodimers for proper binding. Thus, the level of all proneuronal bHLH TFs (here Atoh1 and Neurod1) and available E-proteins as well as their binding preference will determine how much signaling of heterodimers will occur. Importantly, E-proteins can also interact with Hes/Hey factors and the inhibitors of DNA binding (Ids), limiting availability of E-proteins for proneuronal protein heterodimerization, proportionally to the affinity and concentration of all these interactive partners. In essence, the binding properties and frequency of the binding partners will determine whether a cell is differentiating as a neuron/hair cell, a supporting/glial cell, or is continuing proliferation as a prosensory precursor. HC, hair cell and SC, supporting cell. Modified after (Forrest, et al., 2014, Imayoshi and Kageyama, 2014, Pan, et al., 2012, Reiprich and Wegner, 2014).

Fig. 4

The evolution of gene expression at the midbrain–hindbrain boundary (MHB) is shown for deuterostomes. The MHB of vertebrates shows abutting Otx2 and Gbx2 expression (D-G). This stabilizes the expression of Fgf8 (G), which in turn stabilizes the expression of Wnt1 and engrailed (En1). Mutation of Otx2, Gbx2, Fgf8, or Wnt1 eliminates the MHB. Pax2/5/8 are also expressed at the MHB, whereas the expression of Dmbx occurs immediately rostral to the MHB in the midbrain to later expand into the hindbrain and spinal cord (D). Note the partial overlap of Pax2/5/8 with the caudal expression of Otx2 and the rostral expression of Gbx2 (D). Hemichordates (A) have overlapping expression of Gbx, Otx, Irx and En in the rostral trunk. Pax6 abuts Gbx2 whereas Pax2/5/8 overlaps with the caudal expression of Gbx2. Outgroup data suggest that coelenterates have a Dmbx ortholog, thus raising the possibility that hemichordates (A) also have a Dmbx gene. Cephalochordates (B) have no Dmbx expression in the ‘brain’. Otx abuts with Gbx, like in vertebrates. However, Gbx overlaps with Pax2/5/8 and most of Irx3. Urochordates (C) have no Gbx gene but have a Pax2/5/8 and Pax6 configuration comparable to vertebrates. Dmbx overlaps with the caudal end of the Irx3 expression whereas Dmbx expression is rostral to Irx3 in vertebrates. Together these data show that certain gene expression domains are topographically conserved (Foxg1, Hox, Otx), whereas others show varying degrees of overlap. It is conceivable that the evolution of nested expression domains of transcription factors is causally related to the evolution of specific neuronal features such as the evolution of oculomotor and trochlear motoneurons (D,E) around the MHB. Experimental work has demonstrated that the development of these motor centers depends on the formation of the MHB. Adopted from (Beccari, et al., 2013, Fritzsch and Glover, 2006, Pani, et al., 2012)