Abstract
Primary microcephaly is a congenital neurodevelopmental disorder of reduced head circumference and brain volume, with fewer neurons in the cortex of the developing brain due to premature transition between symmetrical and asymmetrical cellular division of the neuronal stem cell layer during neurogenesis. We now show through linkage analysis and whole exome sequencing, that a dominant mutation in ALFY, encoding an autophagy scaffold protein, causes human primary microcephaly. We demonstrate the dominant effect of the mutation in drosophila: transgenic flies harboring the human mutant allele display small brain volume, recapitulating the disease phenotype. Moreover, eye-specific expression of human mutant ALFY causes rough eye phenotype. In molecular terms, we demonstrate that normally ALFY attenuates the canonical Wnt signaling pathway via autophagy-dependent removal specifically of aggregates of DVL3 and not of Dvl1 or Dvl2. Thus, autophagic attenuation of Wnt signaling through removal of Dvl3 aggregates by ALFY acts in determining human brain size.
Highlights
Primary microcephaly has mostly been reported as an autosomal recessive trait coupled with mild to severe intellectual deficit [1, 2]
We demonstrate that normally ALFY attenuates the canonical Wnt signaling pathway via autophagy-dependent removal of aggregates of DVL3 and not of Dvl1 or Dvl2
Hereditary primary microcephaly, a neurodevelopmental disorder in which infants are born with small head circumference and reduced brain volume with intellectual disability, offers insights to the embryonic molecular pathways determining human brain size
Summary
Primary microcephaly has mostly been reported as an autosomal recessive trait coupled with mild to severe intellectual deficit [1, 2]. The RGCs undergo self-renewing cell divisions, later switching from symmetric to asymmetric divisions, giving rise to RGC daughter cells and differentiating basal progenitor (BP) cells which maintain their proliferative state and will later differentiate into neuronal cells [3, 4]. It is believed that premature transition between symmetrical to asymmetrical divisions during brain development is the main cause for primary microcephaly [5,6,7]. This premature transition results in an insufficient number of precursor cells within the neuronal stem cell (NSC) population, and eventually leads to reduced number of neurons in the cortex [5]. Through Drosophila and in-vitro experiments, we show that ALFY controls Wnt signaling by regulating DVL3 aggregation, likely in an autophagy-dependent manner, unveiling novel molecular pathways of normal brain development and primary microcephaly
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