Homophilic binding of the neural cell adhesion molecule CHL1 regulates development of ventral midbrain dopaminergic pathways

Abstract

Abnormal development of ventral midbrain (VM) dopaminergic (DA) pathways, essential for motor and cognitive function, may underpin a number of neurological disorders and thereby highlight the importance of understanding the birth and connectivity of the associated neurons. While a number of regulators of VM DA neurogenesis are known, processes involved in later developmental events, including terminal differentiation and axon morphogenesis, are less well understood. Recent transcriptional analysis studies of the developing VM identified genes expressed during these stages, including the cell adhesion molecule with homology to L1 (Chl1). Here, we map the temporal and spatial expression of CHL1 and assess functional roles of substrate-bound and soluble-forms of the protein during VM DA development. Results showed early CHL1 in the VM, corresponding with roles in DA progenitor migration and differentiation. Subsequently, we demonstrated roles for CHL1 in both axonal extension and repulsion, selectively of DA neurons, suggestive of a role in guidance towards forebrain targets and away from hindbrain nuclei. In part, CHL1 mediates these roles through homophilic CHL1-CHL1 interactions. Collectively, these findings enhance our knowledge of VM DA pathways development, and may provide new insights into understanding DA developmental conditions such as autism spectrum disorders.

Gestational Exposure to Sodium Valproate Disrupts Fasciculation of the Mesotelencephalic Dopaminergic Tract, With a Selective Reduction of Dopaminergic Output From the Ventral Tegmental Area

“…The possibility that ASD might be associated with defective development of the dopaminergic system, has already been raised as a logical suggestion (Bissonette and Roesch, 2016;Alsanie et al, 2017). The present study represents a definite step in this direction, by demonstrating distinct and coherent neuroanatomical and neurochemical changes in the dopaminergic system of mice which were evoked by maternal VPA challenge.…”

“…Additionally, it has been suggested that Semaphorin 3A and 3F participate in navigating DA axons to their target areas (Torre et al, 2010). The role of the cell adhesion molecule CHL1 in early DA progenitor migration and differentiation has also been demonstrated (Alsanie et al, 2017). Notably, Chl1 has been described among the candidate risk genes in ASD families of humans (Salyakina et al, 2011).…”

“…Nevertheless, certain defects of the dopaminergic system are known to be associated with disorders of decision making and sociability, both in experimental animals and in humans. Based on the occurrence of such symptoms in ASD, it has been suggested that an impaired dopaminergic system might be a causal factor in certain forms of the disease (Bissonette and Roesch, 2016;Alsanie et al, 2017). The coherent neuroanatomical and neurochemical results of the present study point in the same direction: diminished dopaminergic input to the ventrobasal telencephalon from a critical time point of embryonic development (E13-E14) onwards may hinder the maturation and patterning of certain brain centers earmarked for decision making and sociability, and cause the observed (Supplementary Figure S1) impairment in social preference.…”

Axonal Growth of Midbrain Dopamine Neurons is Modulated by the Cell Adhesion Molecule ALCAM Through Trans-Heterophilic Interactions with L1cam, Chl1, and Semaphorins

“…Currently, the only binding partner described for Alcam in neurons is L1cam, identified in immunoprecipitation assays in chick brain and also as a feature of retinal ganglion neurites showing growth preference for Alcam coated substrates in vitro (DeBernardo and Chang, 1996;Avci et al, 2004) (Buhusi et al, 2009). Chl1 is a CAM with close homology to L1cam and has previously been shown to cooperate with L1cam to facilitate thalamocortical pathfinding (Demyanenko et al, 2011), is expressed in mDA neuroblasts (Bye et al, 2015), and can regulate mDA axonal growth and guidance as both a soluble and bound substrate (Alsanie et al, 2017). Both L1cam and Chl1 were expressed in mDA neurons, notably including prominent expression in growth cones, and in TH ϩ fibers throughout the major mDA growth pathways during the peak period of axonal growth.…”

“…This led us to examine the potential for L1cam on mDA axons to bind Alcam substrate in trans to facilitate the observed regulation of axon growth. We also examined Chl1 in the same context, a structurally and functionally related member of the L1cam family with high homology to L1cam that we have previously reported as being expressed in mDA neurons and contributing to the development of mDA pathways (Bye et al, 2015;Alsanie et al, 2017).…”