The folate metabolic enzyme ALDH1L1 is restricted to the midline of the early CNS, suggesting a role in human neural tube defects

Abstract

Folate supplementation prevents up to 70% of human neural tube defects (NTDs), although the precise cellular and metabolic sites of action remain undefined. One possibility is that folate modulates the function of metabolic enzymes expressed in cellular populations involved in neural tube closure. Here we show that the folate metabolic enzyme ALDH1L1 is cell-specifically expressed in PAX3-negative radial glia at the midline of the neural tube during early murine embryogenesis. Midline restriction is not a general property of this branch of folate metabolism, as MTHFD1 displays broad and apparently ubiquitous expression throughout the neural tube. Consistent with previous work showing antiproliferative effects in vitro, ALDH1L1 upregulation during central nervous system (CNS) development correlates with reduced proliferation and most midline ALDH1L1(+) cells are quiescent. These data provide the first evidence for localized differences in folate metabolism within the early neural tube and suggest that folate might modulate proliferation via effects on midline Aldh1l1(+) cells. To begin addressing its role in neurulation, we analyzed a microdeletion mouse strain lacking Aldh1l1 and observed neither increased failure of neural tube closure nor detectable proliferation defects. Although these results indicate that loss-of-function Aldh1l1 mutations do not impair these processes in mice, the specific midline expression of ALDH1L1 and its ability to dominantly suppress proliferation in a folate responsive manner may suggest that mutations contributing to disease are gain-of-function, rather than loss-of-function. Moreover, a role for loss-of-function mutations in human NTDs remains possible, as Mthfr null mice do not develop NTDs even though MTHFR mutations increase human NTD risk.

A Transcriptome Database for Astrocytes, Neurons, and Oligodendrocytes: A New Resource for Understanding Brain Development and Function

“…One such gene that fit these criteria is the aldehyde dehydrogenase 1 family, member L1 (Aldh1L1) gene, also known as 10-formyltetrahydrofolate dehydrogenase (FDH) (Cook et al, 1991;Anthony and Heintz, 2007). ISH for this gene indicated that its mRNA is expressed throughout the CNS in a pattern consistent with pan-astrocyte expression (Fig.…”

Astrocytes and disease: a neurodevelopmental perspective

“…Recently, the application of gene expression profiling to purified astrocyte populations (Cahoy et al 2008;Doyle et al 2008;Fu et al 2009;Rowitch and Kriegstein 2010) has revealed several potential new markers, such as the gene encoding the folate metabolic enzyme Aldh1L1 (Anthony and Heintz 2007;Cahoy et al 2008;Ballas et al 2009;. Iterative use of such approaches may yield better methods for isolating and analyzing developing and mature astrocytes.…”

Towards improved animal models of neonatal white matter injury associated with cerebral palsy

“…The GENSAT project (http://www.gensat. org/index.html) has also provided many new mouse strains that express the fluorescent marker green fluorescent protein (GFP) under the control of regulatory sequences that are specific to glial lineages, better enabling their identification in slice culture and in vivo (Anthony and Heintz, 2007).…”