cells Review New Molecular Players in the Development of Callosal Projections Ray Yueh Ku 1 and Masaaki Torii 1,2,* 1 Center for Neuroscience Research, Children’s Research Institute, Children’s National Hospital, Washington, DC 20010, USA 2 Department of Pediatrics, Pharmacology and Physiology, School of Medicine and Health Sciences, The George Washington University, Washington, DC 20052, USA * Correspondence: [email protected] Abstract: Cortical development in humans is a long and ongoing process that continuously modifies the neural circuitry into adolescence. This is well represented by the dynamic maturation of the corpus callosum, the largest white matter tract in the brain. Callosal projection neurons whose long-range axons form the main component of the corpus callosum are evolved relatively recently with a substantial, disproportionate increase in numbers in humans. Though the anatomy of the corpus callosum and cellular processes in its development have been intensively studied by experts in a variety of fields over several decades, the whole picture of its development, in particular, the molecular controls over the development of callosal projections, still has many missing pieces. This review highlights the most recent progress on the understanding of corpus callosum formation with a special emphasis on the novel molecular players in the development of axonal projections in the corpus callosum. Keywords: corpus callosum; callosal projections; cerebral cortex; development; cortical neurons 1. Introduction—The Corpus Callosum Citation: Ku, R.Y.; Torii, M. New The corpus callosum (CC) is the largest white matter tract that connects two cerebral Molecular Players in the Development hemispheres of placental animals. The communication via approximately two hundred of Callosal Projections. Cells 2021, 10, million callosal axons allows efficient information exchange between the two hemispheres, 29. https://dx.doi.org/10.3390/ coordinating our higher-order motor, sensory, and cognitive tasks [1,2]. The human CC is cells10010029 anatomically divided into several regions that topographically connect two hemispheres: The anterior-most rostrum, genu, body, isthmus, and splenium at the posterior end, Received: 5 December 2020 while the mouse CC is usually divided into three regions: genu, body, and splenium Accepted: 23 December 2020 (Figure1A,B). Along the anterior–posterior axis, the genu and rostrum connect the frontal Published: 26 December 2020 and premotor regions of the cerebral cortex, the body conjoins the motor, somatosensory, and parietal regions, while the splenium links the temporal and occipital cortices on both Publisher’s Note: MDPI stays neu- sides [3–5]. Although the organization of the CC is defined anatomically, corresponding tral with regard to jurisdictional claims functional topography has been found based on imaging studies and studies on patients in published maps and institutional who underwent callosal resection, as well as studies using animal models. For example, affiliations. neuronal signals for the motor function pass through the genu, while somatosensory inputs go through posterior body of CC. Axons in isthmus are in charge of transmitting auditory signals, and visual information via splenium [6,7]. Dorsal and ventral parts of the CC then Copyright: © 2020 by the authors. Li- connect the medial and lateral cortical regions, respectively [8–10] (Figure1C). Different censee MDPI, Basel, Switzerland. This parts of the CC, therefore, consist of axonal projections from different cortical regions. article is an open access article distributed In addition, callosal projections from each cortical region also include axons of cortical under the terms and conditions of the neurons in multiple cortical layers [11–13]. It is estimated that 80% of callosal axons come Creative Commons Attribution (CC BY) from neurons in layer II/III, and 20% are from neurons in layer V in the mature brain [11]. license (https://creativecommons.org/ licenses/by/4.0/). Cells 2021, 10, 29. https://dx.doi.org/10.3390/cells10010029 https://www.mdpi.com/journal/cells Cells 2021, 10, x FOR PEER REVIEW 2 of 18 Cells 2021, 10, 29 2 of 17 FigureFigure 1. 1.The The organization organization of the mouse of the corpus mouse callosum corpus (CC). callosum Dorsal (A ),(CC). midsagittal Dorsal (B), ( andA), coronalmidsagittal (C) views (B of), theand CC. Callosal axon projections from each cortical hemisphere cross the midline and primarily connect with homotopic coronal (C) views of the CC. Callosal axon projections from each cortical hemisphere cross the cortical regions in a topographic manner, by which projections from anterior and posterior cortical regions form anterior midlineand posterior and parts primarily of the CC, connect respectively with (represented homotopic by rainbow cortical colors regions in A and inB). a Callosal topographic projections manner, from the medial by which projectionsand lateral regions from of theanterior cortex formand the posterior dorsal and cortical ventral portions regions of theform CC, anterior respectively and (C). posterior parts of the CC, respectively (represented by rainbow colors in A and B). Callosal projections from the medial With these highly precise neuronal connections, the CC integrates inputs from left and lateral regions of the cortex form the dorsal and ventral portions of the CC, respectively (C). and right sides of the body for central processing and coordinates bimanual motor move- ments [14]. The presence of an intact, functional CC facilitates signal exchange between With these highlythe two precise hemispheres neuronal [15]. The connecti integrityons, and the the efficiency CC integrates of interhemispheric inputs information from left and right sides of theexchange body isfor also central strongly processing correlated with and social-cognitive coordinates functions bimanual [16–18 ].motor As such, move- if the formation of CC is compromised (e.g., agenesis, dysgenesis, or hypoplasia) by genetic ments [14]. The presencemutations of or an prenatal intact, exposure functi toonal environmental CC facilitates insults [19 signal–23], the exchange abnormal CC between leads to the two hemispheresvarious [15]. transientThe integrity and permanent and the symptoms. efficiency These of include interhemispheric impairment in problem information solving, exchange is also stronglydyslexia, correlated ataxia, apraxia, with alien social-cognitive limb, agraphia, paresis, functions and mutism [16,17,18]. [1,24]. Understand-As such, if ing the mechanisms of CC development is therefore critical to maintain the health and the formation of CCwellbeing is compromised of human life. (e.g., agenesis, dysgenesis, or hypoplasia) by genetic mutations or prenatal exposureIn the following to environm sections, weental will first insults review the[19,20,21,22,23], findings on prenatal the development abnormal CC leads to variousof transient callosal projection, and permanen and move ontot symptoms. the less understood These postnatal include processes impairment of callosal in projection development. As this review focuses on the molecular mechanisms underlying problem solving, dyslexia,these events, ataxia, we leave apraxia, out some alien important limb, topics agraphia, on CC development, paresis, and including mutism the [1,24]. Understandingformation the mechanisms of midline glial of structure,CC devel myelination,opment is and therefore activity-dependent critical to refinement, maintain the health and wellbeingand instead of human only present life. informative reviews on these topics. In the following2. Prenatalsections, Development we will first of Callosal review Projections the findings on prenatal development of callosal projection, andThe formationmove onto of the the CC beginsless understood with the projection postnatal of pioneer processes fibers from theof cingulatecallosal projection development.and rostrolateral As this review cortices [focuses25–27] at aroundon the the molecular 12th week ofmechanisms gestation (GW) underlying in humans, followed by formation of the genu [20,28]. The fusion of these different parts of the CC these events, we leavecompletes out some at around important GW14, and topics the CC on expands CC development, as the brain increases including in size the [29 ,30for-]. mation of midline glialThough structure, each region growsmyelinat at differention, and rates, theactivity-dependent overall volume of the CCrefinement, increases rapidly and instead only presentin informative early development reviews (GW19–21), on these and continues topics. to grow at a slower rate until it reaches a plateau at around GW33 [29,31,32]. Our current understanding of prenatal development of the CC at the molecular and 2. Prenatal Developmentcellular levelsof Callosal have mainly Projections come from studies using animal models such as mice, cats, The formation andof the monkeys, CC begins while studies with of the fetal pr specimensojection have of supplied pioneer the fibers anatomical from understanding the cingu- of CC development in humans. Since there are many excellent reviews on the prenatal late and rostrolateraldevelopment cortices [25,26,27] of the CC available at around already the (e.g., 12th [11,33 ,week34]), we of will gestation review this (GW) topic focusing in hu- mans, followed by formationon the latest discoveries.of the genu [20,28]. The fusion of these different parts of the CC completes at around GW14, and the CC expands as the brain increases in