During embryonic development, morphogens act as graded positional cues to dictate cell fate specification and tissue patterning. Recent findings indicate that morphogen gradients also serve to guide axonal pathfinding during development of the nervous system. These findings challenge our previous notions about morphogens and axon guidance molecules, and suggest that these proteins, rather than having sharply divergent functions, act more globally to provide graded positional information that can be interpreted by responding cells either to specify cell fate or to direct axonal pathfinding. This review presents the roles identified for members of three prominent morphogen families--the Hedgehog, Wnt and TGFbeta/BMP families--in axon guidance, and discusses potential implications for the molecular mechanisms underlying their guidance functions.
"In this model, the axons are born in the dorsal region of the spinal cord and extend ventrally towards the FP. Commissural axons are initially repelled by members of the bone morphogenetic protein (BMP) and wingless-related mouse mammary tumor virus integration site (Wnt) families which emanate from the RP and towards the ventral spinal cord, where they are attracted to the FP by combinations of different guidance cues such as Netrin and Shh (Butler and Dodd, 2003; Charron and Tessier-Lavigne, 2005). There are also repellent cues, such as members of the Eph/ephrin family, which prevent ipsilateral axons from midline crossing (Nawabi and Castellani, 2011). "
[Show abstract][Hide abstract] ABSTRACT: Bilaterally symmetric organisms need to exchange information between the two sides of their bodies in order to integrate sensory inputs and coordinate motor control. This exchange occurs through commissures formed by neurons that project axons across the midline to the contralateral side of the central nervous system. The posterior commissure is the first transversal axonal tract of the embryonic vertebrate brain. It is located in the dorsal portion of the prosomere 1, at the caudal diencephalon. The axons of the posterior commissure principally come from neurons of ventrolateral and dorsolateral pretectal nuclei (parvocellular and magnocellular nucleus of the posterior commissure, respectively) that extend their axons toward the dorsal region. The trajectory of these axons can be divided into the following three stages: (1) dorsal axon extension towards the lateral roof plate; (2) fasciculation in the lateral roof plate; and (3) midline decision of turning to the ipsilateral side or continuing to the opposite side. The mechanisms and molecules that guide the axons during these steps are unknown. In the present work, immunohistochemical and in situ hybridization analyses were performed, with results suggesting the participation of EphA7 in guiding axons from the ventral to the dorsal region of the prosomere 1 through the generation of an axonal corridor limited by repulsive EphA7 walls. At the lateral roof plate, the axons became fasciculated in presence of SCO-spondin until reaching the midline. Finally, EphA7 expression was observed in the diencephalic midline roof plate, specifically in the region where some axons turn to the ipsilateral side, suggesting its participation in this decision. In summary, the present work proposes a mechanism of posterior commissure formation orchestrated by the complementary expression of the axon guidance cues SCO-spondin and EphA7.
Frontiers in Neuroanatomy 06/2014; 8:49. DOI:10.3389/fnana.2014.00049 · 3.54 Impact Factor
"Sbacchi et al. (2010) used gene ontogeny and pathway analyses to determine common functions of duplicated or deleted genes lying within CNVs derived from four large ASD microarray data sets. They identified a substantial number of canonical axonal guidance genes as well as certain BMP, Wnt, Engrailed morphogens which are also known to participate in axon guidance (Charron and Tessier-Lavigne, 2005) and linked to ASD by previous studies (Kalkman, 2012). Hussman et al. (2011), similarly identified a substantial group of ASD candidate genes involved in neurite outgrowth by genome-wide association. "
[Show abstract][Hide abstract] ABSTRACT: Current theories concerning the cause of autism spectrum disorders (ASDs) have converged on the concept of abnormal development of brain connectivity. This concept is supported by accumulating evidence from functional imaging, diffusion tensor imaging, and high definition fiber tracking studies which suggest altered microstructure in the axonal tracts connecting cortical areas may underly many of the cognitive manifestations of ASD. Additionally, large-scale genomic studies implicate numerous gene candidates known or suspected to mediate neuritic outgrowth and axonal guidance in fetal and perinatal life. Neuropathological observations in postmortem ASD brain samples further support this model and include subtle disturbances of cortical lamination and subcortical axonal morphology. Of note is the relatively common finding of poor differentiation of the gray-white junction associated with an excess superficial white matter or "interstitial" neurons (INs). INs are thought to be remnants of the fetal subplate, a transient structure which plays a key role in the guidance and morphogenesis of thalamocortical and cortico-cortical connections and the organization of cortical columnar architecture. While not discounting the importance of synaptic dysfunction in the etiology of ASD, this paper will briefly review the cortical abnormalities and genetic evidence supporting a model of dysregulated axonal growth and guidance as key developmental processes underlying the clinical manifestations of ASD.
Frontiers in Human Neuroscience 10/2013; 7:671. DOI:10.3389/fnhum.2013.00671 · 2.99 Impact Factor
"3.3. Shh/BMP7 mediate the repulsive effects of the ventral midline Morphogens can contribute to axonal pathfinding in various systems  . Our previous studies have shown that FGF10 deriving from the MVM of the chick hypothalamus plays an important role in guiding hypothalamic axons to turn into the Fig. 2. AVM and PVM hypothalamic explants repel hypothalamic axons. "
[Show abstract][Hide abstract] ABSTRACT: Hypothalamus plays a key role in homeostasis, and functions of the hypothalamus depend on the accurate trajectory of hypothalamic neuroendocrine axons. Thus, understanding the guidance of hypothalamic neuroendocrine axons is crucial for knowing how hypothalamus works. Previous studies suggest FGF10 deriving from the medial ventral midline of the hypothalamus plays an important role in axon guidance of the developing hypothalamus. Here we show that Shh and BMP7, which are from the anterior and posterior hypothalamic ventral midline respectively, together repel hypothalamic axons towards the medial ventral midline.
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