Evolution and development of interhemispheric connections in the vertebrate forebrain

Abstract

Axonal connections between the left and right sides of the brain are crucial for bilateral integration of lateralized sensory, motor, and associative functions. Throughout vertebrate species, forebrain commissures share a conserved developmental plan, a similar position relative to each other within the brain and similar patterns of connectivity. However, major events in the evolution of the vertebrate brain, such as the expansion of the telencephalon in tetrapods and the origin of the six-layered isocortex in mammals, resulted in the emergence and diversification of new commissural routes. These new interhemispheric connections include the pallial commissure, which appeared in the ancestors of tetrapods and connects the left and right sides of the medial pallium (hippocampus in mammals), and the corpus callosum, which is exclusive to eutherian (placental) mammals and connects both isocortical hemispheres. A comparative analysis of commissural systems in vertebrates reveals that the emergence of new commissural routes may have involved co-option of developmental mechanisms and anatomical substrates of preexistent commissural pathways. One of the embryonic regions of interest for studying these processes is the commissural plate, a portion of the early telencephalic midline that provides molecular specification and a cellular scaffold for the development of commissural axons. Further investigations into these embryonic processes in carefully selected species will provide insights not only into the mechanisms driving commissural evolution, but also regarding more general biological problems such as the role of developmental plasticity in evolutionary change.

Keywords: anterior commissure; axon guidance; commissural plate; comparative neuroanatomy; corpus callosum; hippocampal commissure.

Figure 1

Conservation of a general organization of vertebrate brain development. (A) Diagram of an early stage of brain development in a model vertebrate, equivalent to mouse E11, showing the principal regions of morphogen expression. Rostral expression of Fgf defines the anterior neural ridge (ANR). The zona limitans intrathalamica (ZLI) is defined by a narrow band of Shh expression, with Fgf and BMP/Wnt coexpression dorsally at the border between the presumptive telencephalon and diencephalon. Caudally, the isthmic organizer (IsO) marks the boundary between the midbrain and hindbrain territories. (B) Midsagittal schematic of a model vertebrate brain at a later stage, equivalent to mouse E14, showing the position of the first axon bundles that form during development, including the posterior commissure (cp) and post-optic commissure (poc), followed by the anterior commissure (ac), habenular commissure (hbc) and optic chiasm (oc). Dorsal is to the top and rostral to the left.

Figure 2

Conservation of commissural systems across adult vertebrate species. (A) Commissures in non-tetrapod species. Note the conserved position of commissures relative to each other within and between species, commissures are color-coded according to homology hypotheses. The commissura interbulbaris (cib) and anterior commissure (ac) of lampreys and hagfish are depicted here with a unique color (orange) to indicate the uncertainty of definitive homology with other vertebrates. (B) Tetrapods are characterized by the evolution of a distinct pallial commissure (cpal) in close dorsal proximity with the anterior commissure. The mammalian homolog of the pallial commissure is known as hippocampal commissure (hc). The corpus callosum (cc) is an evolutionary innovation of placental mammals, located dorsal to the hippocampal commissure. Phylogenetic relationships between species are depicted with dendrograms below species name. 3V, third ventricle; Cb, cerebellum; cp, posterior commissure; hbc, habenular commissure; IsoC, isocortex; OB, olfactory bulb; oc, optic chiasm; poc, post-optic commissure; Tel, telencephalon; Th, thalamus; TM, tectum mesencephali.

Figure 3

Evolution of telencephalic commissures in tetrapods. Coronal schematics of tetrapod brains show the close association between the pallial commissure (cpal) and the anterior commissure (ac), bilaterally connecting the medial pallium (MP) and olfactory recipient structures, respectively. In the opossum all isocortical (IsoC) and piriform (Pir) commissural projections cross through the anterior commissure (ac) after coursing through the external capsule (ec). In the kangaroo, as in other diprotodont marsupials, axons from more dorsal regions of the isocortex course through the internal capsule (ic) toward the anterior commissure, forming the fasciculum aberrans (fa). Hippocampal neurons decussate through the hippocampal commissure (hc). In tenrecs, as in other basal placentals with a small IsoC/Pir ratio, the corpus callosum (cc) is a small structure located immediately above the hippocampal commissure. Developmental studies in mice and humans have shown that all three commissures arise from the commissural plate, forming a single plane of morphogenic patterning. GW, gestational week; DP, dorsal pallium; LP, lateral pallium.

Figure 4

Morphogenic patterning at the commissural plate. (A) Discrete regions of the early telencephalic midline of mice at E 11.5 express diffusible Wnt/Bmp, Fgf, and Shh proteins, as revealed by mRNA expression studies. (B) The differential concentration of each morphogen at any point in space results in distinct intracellular signaling outcomes, generating different cell fates. (C) A midsagittal schematic of the embryonic mouse brain showing the plane of section (D,F) defined by telencephalic commissures, known as the commissural plate. (D) Transverse section through the presumptive commissural plate at E14 shows the spatial extent of morphogen expression, mostly defining pallial, septal, and preoptic domains. (E) In general, morphogen interactions are reciprocally repressive between the pallial and subpallial regions; numbers denote references providing evidence for each interaction (see below for reference key). Further definition of the medial pallium, septum and preoptic areas is achieved by the induction of transcription factors such as Msx1/2, Emx1/2 (pallial), Zic2, Lhx5, Vax1 (septal), Six3 and Nkx2.1 (preoptic). (F) Dorso-ventral patterning domains also define the dorso-ventral level at which the three telencephalic commissures will cross within the caudal telencephalic midline. References: ¹Storm et al., ; ²Ohkubo et al., ; ³Fernandes et al., ; ⁴Hebert et al., ; ⁵Shimogori et al., ; ⁶Gunhaga et al., ; ⁷Okada et al., ; ⁸Geng et al., ; ⁹Jeong et al., ; ¹⁰Lee et al., .

Figure 5

Cellular architecture of the telencephalic midline and callosal development. (A) The ventral-most boundary of the corpus callosum is established by glial wedge cells, as cingulate pioneering axons first cross the midline at E15, while the more laterally located isocortical axons grow toward the midline following cingulate axons. (B) At E16, a small number of isocortical axons have crossed the midline, and the indusium griseum glia and midline zipper glia are now detectable with Gfap immunohistochemistry. The indusium griseum glia provide the dorsal boundary of the corpus callosum. In addition, cells of the subcallosal sling begin to migrate toward the midline, just beneath the corpus callosum. (C) By E17, isocortical axons have started crossing the midline, and cingulate pioneering axons are projecting to homotopic targets in the contralateral hemisphere. Midline crossing of callosal axons continues during early postnatal stages in mice.