DSCAM and DSCAML1 regulate the radial migration and callosal projection in developing cerebral cortex

Zhang, Lei; Huang, Ying; Chen, Jia-Yin; Ding, Yu; Song, Ning‐Ning

doi:10.1016/j.brainres.2014.10.060

Cited by 26 publications

(31 citation statements)

References 30 publications

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“…Neurite outgrowth of DRG neurons from Dscam 2/2 mice plated on a DSCAM substrate is also significantly impaired (Amano et al, 2009). In addition, two recent studies have demonstrated that Dscam knockdown in mouse cortical neurons results in a significant reduction in axon length (Zhang et al, 2014) and netrin-1-induced axon branching (Huang et al, 2015).…”

Section: Axon Guidance Dscam and Down Syndromementioning

confidence: 99%

Netrin‐1 induces local translation of down syndrome cell adhesion molecule in axonal growth cones

Jain

Welshhans

2015

Developmental Neurobiology

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Down syndrome cell adhesion molecule (DSCAM) plays an important role in many neurodevelopmental processes such as axon guidance, dendrite arborization, and synapse formation. DSCAM is located in the Down syndrome trisomic region of human chromosome 21 and may contribute to the Down syndrome brain phenotype, which includes a reduction in the formation of long-distance connectivity. The local translation of a select group of mRNA transcripts within growth cones is necessary for the formation of appropriate neuronal connectivity. Interestingly, we have found that Dscam mRNA is localized to growth cones of mouse hippocampal neurons, and is dynamically regulated in response to the axon guidance molecule, netrin-1. Furthermore, netrin-1 stimulation results in an increase in locally translated DSCAM protein in growth cones. Deleted in colorectal cancer (DCC), a netrin-1 receptor, is required for the netrin-1-induced increase in Dscam mRNA local translation. We also find that two RNA-binding proteins-fragile X mental retardation protein (FMRP) and cytoplasmic polyadenylation element binding protein (CPEB)-colocalize with Dscam mRNA in growth cones, suggesting their regulation of Dscam mRNA localization and translation. Finally, overexpression of DSCAM in mouse cortical neurons results in a severe stunting of axon outgrowth and branching, suggesting that an increase in DSCAM protein results in a structural change having functional consequences. Taken together, these results suggest that netrin-1-induced local translation of Dscam mRNA during embryonic development may be an important mechanism to regulate axon growth and guidance in the developing nervous system. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 76: 799-816, 2016.

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Section: Axon Guidance Dscam and Down Syndromementioning

confidence: 99%

Netrin‐1 induces local translation of down syndrome cell adhesion molecule in axonal growth cones

Jain

Welshhans

2015

Developmental Neurobiology

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“…At the cellular level, DSCAMs promote avoidance between neurites of the same cell or between similar cell types. DSCAMs are also involved in the regulation of cell death, synaptic adhesion, axon outgrowth, axonal refinement, and dendritic growth 3, 4, 5, 6, 7, 8 . However, it is still unclear how the sum of these cellular functions contribute to neural circuit activity, behavior, and human disorders.…”

Section: Introductionmentioning

confidence: 99%

Zebrafish Dscaml1 is Essential for Retinal Patterning and Function of Oculomotor Subcircuits

Ramirez

Wang

et al. 2019

Preprint

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41Down Syndrome Cell Adhesion Molecules (dscam and dscaml1) are essential regulators of neural 42 circuit assembly, but their roles in vertebrate neural circuit function are still mostly unexplored. We 43 investigated the role of dscaml1 in the zebrafish oculomotor system, where behavior, circuit 44 function, and neuronal activity can be precisely quantified. Loss of zebrafish dscaml1 resulted in 45 deficits in retinal patterning and light adaptation, consistent with its known roles in mammals. 46Oculomotor analyses showed that mutants have abnormal gaze stabilization, impaired fixation, 47 disconjugation, and faster fatigue. Notably, the saccade and fatigue phenotypes in dscaml1 mutants 48 are reminiscent of human ocular motor apraxia, for which no animal model exists. Two-photon 49 calcium imaging showed that loss of dscaml1 leads to impairment in the saccadic premotor pathway 50 but not the pretectum-vestibular premotor pathway, indicating a subcircuit requirement for 51 dscaml1. Together, we show that dscaml1 has both broad and specific roles in oculomotor circuit 52 function, providing a new animal model to investigate the development of premotor pathways and 53

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“…Knockdown of these genes in vivo also causes defects in radial migration and decreased morphology of the S1/S2 projection, labelled with in utero electroporation (Zhang et al, 2015).…”

Section: Evidence From Knockdown Experimentsmentioning

confidence: 99%

“…Indeed, the in vitro work on dissociated cells from the entire cerebral cortex in several of the above studies (e.g. Lu et al, 2013;Zhang et al, 2015) indicates that many of these molecular mechanisms may not be callosal-specific. Similarly, as discussed above, it has already been well established that reducing sensory input or intrinsic cortical activity affects contralateral callosal targeting, and thus any manipulation that has a side-effect of changing activity properties of transfected neurons may subsequently cause defects in this process, without necessarily being specific to the system.…”

Section: Barriers To Elucidating the Molecular Mechanismsmentioning

confidence: 99%

“…The most specific and commonly utilised neuronal layer labelled using this method is L2/3, which can be achieved by electroporating at embryonic day (E) 15.5 in mice. This method has already been widely used to study many aspects of callosal development, including cell migration and projection (Mizuno et al, 2015;Zhang et al, 2015), axonal patterning (Sehara et al, 2010;Sehara et al, 2012), contralateral targeting (Mizuno et al, 2007;Mizuno et al, 2010;Suárez et al, 2014b), axon branching Lu et al, 2013) and functional connectivity patterns . The callosum connecting the somatosensory cortex of mice (especially the barrel cortex) is a particularly suitable model system for commissural investigations due to its point-to-point topographical arrangement from the sensory periphery to the cortex, stereotypical cytoarchitectural features and full decussation.…”

Section: Introductionmentioning

confidence: 99%

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Contralateral targeting of the corpus callosum

Fenlon¹

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During development, the brain establishes billions of precise connections in order to perform its myriad functions. The largest of these connections in placental mammals is the corpus callosum, which is a large bundle of axons linking the two cortical hemispheres of the brain. Absence or gross malformation of this structure is a relatively common developmental disorder in humans, producing symptoms ranging from severe to mild cognitive, emotional and motor deficits. However, recent evidence suggests that the corpus callosum can also display subtle malformations that are not visible with traditional magnetic resonance imaging methods, and that these may be involved in neurodevelopmental disorders such as autism and schizophrenia. The possibility of callosal misconnectivity arising independently of the widely-studied process of midline crossing highlights the need to investigate other less well-understood stages of callosal development. One such process that may be disrupted after normal midline crossing of the corpus callosum is contralateral targeting, where axons must locate, innervate and stabilize in their appropriate contralateral cortical targets.This thesis focuses on understanding the normal process of contralateral targeting, as well as the nature of its dependence on neuronal activity and the molecular mechanisms that regulate it. To investigate these topics, diverse approaches including in utero electroporation, stereotaxic brain injection, sensory deprivation paradigms, tissuespecific RNA extraction and RNA sequencing were used in the mouse somatosensory cortex model system of callosal connectivity. Novel patterns and processes of normal contralateral targeting were identified, as well as distinct periods of region-specific activitydependent and -independent axonal exuberance. Contralateral callosal targeting was also shown to be not just dependent on neuronal activity, but rather a balance of spatially symmetric activity between the two cortical hemispheres. The molecular mechanisms underlying activity-dependent and -independent stages of contralateral callosal targeting were also investigated, and a novel technique to extract RNA from an electroporated population of cell bodies and/or their callosal axons was developed to facilitate this study in the future.These results constitute fundamental insights into the process of contralateral callosal targeting, as well as some of the mechanisms that may lead to its disruption. This work provides solid foundations for future studies to build upon, and may ultimately help us to better understand subtle human disorders of neuronal connectivity.3

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DSCAM and DSCAML1 regulate the radial migration and callosal projection in developing cerebral cortex

Cited by 26 publications

References 30 publications

Netrin‐1 induces local translation of down syndrome cell adhesion molecule in axonal growth cones

Netrin‐1 induces local translation of down syndrome cell adhesion molecule in axonal growth cones

Zebrafish Dscaml1 is Essential for Retinal Patterning and Function of Oculomotor Subcircuits

Contralateral targeting of the corpus callosum

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