Abstract
Members of the AFF (AF4/FMR2) family of putative transcription factors are involved in infant acute leukaemia and intellectual disability (ID), although very little is known about their transcriptional targets. For example, deletion of human lymphoid nuclear protein related to AF4/AFF member 3 (LAF4/AFF3) is known to cause severe neurodevelopmental defects, and silencing of the gene is also associated with ID at the folate-sensitive fragile site (FSFS) FRA2A; yet the normal function of this gene in the nervous system is unclear. The aim of this study was to further investigate the function of Laf4 in the brain by focusing on its role in the cortex. By manipulating expression levels in organotypic slices, we demonstrate here that Laf4 is required for normal cellular migration in the developing cortex and have subsequently identified Mdga2, an important structural protein in neurodevelopment, as a target of Laf4 transcriptional activity. Furthermore, we show that the migration deficit caused by loss of Laf4 can be partially rescued by Mdga2 over-expression, revealing an important functional relationship between these genes. Our study demonstrates the key transcriptional role of Laf4 during early brain development and reveals a novel function for the gene in the process of cortical cell migration relevant to the haploinsufficiency and silencing observed in human neurodevelopmental disorders.
Highlights
Mixed lineage leukaemia (MLL) gene rearrangements occur in approximately 70 percent of infant acute lymphoblastic leukaemia (ALL) patients [1]
By E13.5, Laf4 is highly expressed in the developing brain, and as embryogenesis proceeds, expression becomes localized to the subventricular zone (SVZ) and the dorsal cortex by E15.5 (Figures 1A and B); importantly, this corresponds to a developmental window during which intermediate progenitor cells in the SVZ proliferate and subsequently migrate to form the upper layers of the cortex [29]
Laf4 is the first AFF member identified as a regulator of cerebral cortex development
Summary
Mixed lineage leukaemia (MLL) gene rearrangements occur in approximately 70 percent of infant acute lymphoblastic leukaemia (ALL) patients [1]. LAF4 has been found to be abnormally expressed in approximately 20 percent of breast cancers, suggesting that it may act as a proto-oncogene [4]. A human microdeletion of 500 kb on chromosome 2q11.1 encompassing only the LAF4 gene has been detected by array comparative genomic hybridization on peripheral lymphocytes [5]. The patient presented with developmental delay, seizures, urogenital and limb defects and died at four months of age after numerous repeated apnoeic episodes [5]. A recent study identified a CGG repeat expansion in the promoter of LAF4 at an autosomal folatesensitive fragile site (FSFS) named FRA2A that is associated with
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