Quantitative trait locus mapping identifies a locus linked to striatal dopamine and points to collagen IV alpha‐6 chain as a novel regulator of striatal axonal branching in mice

Abstract

Dopaminergic neurons (DA neurons) are controlled by multiple factors, many involved in neurological disease. Parkinson's disease motor symptoms are caused by the demise of nigral DA neurons, leading to loss of striatal dopamine (DA). Here, we measured DA concentration in the dorsal striatum of 32 members of Collaborative Cross (CC) family and their eight founder strains. Striatal DA varied greatly in founders, and differences were highly heritable in the inbred CC progeny. We identified a locus, containing 164 genes, linked to DA concentration in the dorsal striatum on chromosome X. We used RNAseq profiling of the ventral midbrain of two founders with substantial difference in striatal DA–C56BL/6 J and A/J—to highlight potential protein‐coding candidates modulating this trait. Among the five differentially expressed genes within the locus, we found that the gene coding for the collagen IV alpha 6 chain (Col4a6) was expressed nine times less in A/J than in C57BL/6J. Using single cell RNA‐seq data from developing human midbrain, we found that COL4A6 is highly expressed in radial glia‐like cells and neuronal progenitors, indicating a role in neuronal development. Collagen IV alpha‐6 chain (COL4A6) controls axogenesis in simple model organisms. Consistent with these findings, A/J mice had less striatal axonal branching than C57BL/6J mice. We tentatively conclude that DA concentration and axonal branching in dorsal striatum are modulated by COL4A6, possibly during development. Our study shows that genetic mapping based on an easily measured Central Nervous System (CNS) trait, using the CC population, combined with follow‐up observations, can parse heritability of such a trait, and nominate novel functions for commonly expressed proteins.

Neuronal Phenotype of col4a1 and col25a1: An Intriguing Hypothesis in Vertebrates Brain Aging

“…In agreement with our findings, it has been previously reported that the expression of collagen type IV increases during aging in the human brain, where it accumulates in the basal lamina of cerebral microvessels, therefore, it is considered as a major risk factor for the development of stroke and vascular dementia [9]. Notably, in mouse brain, expression levels of collagen type IV α6 chain followed the expression of Sox2, a key regulator of neurogenesis [37,38]. In the brain of N. furzeri, we also observed a parallel age-related increase in col4a1 and sox2, showing that the functional relationship of these two genes might be conserved in this model organism, in which they could possibly be implicated in neuronal physiology (e.g., axon guidance and neurite outgrowth), as already shown in zebrafish [12].…”

Nigral Transcriptomic Profiles in Engrailed-1 Hemizygous Mouse Models of Parkinson’s Disease Reveal Upregulation of Oxidative Phosphorylation-Related Genes Associated with Resistance to Dopaminergic Neurodegeneration

“…This suggests that the observed resistance to the PD-like phenotype in C57- En1 +/- mice is not due to a neuronal reserve in the SNpc exerting a buffering effect, but rather due to other involved mechanisms. Instead of SNpc cell numbers, cellular function and morphology may be more important for motor function, and the Collaborative Crossing Consortia reported that low performance on motor test was associated with striatal axonal branching rather than TH + area in the SNpc (Thomas et al, 2021).…”