Connecting neurodevelopment to neurodegeneration: a spotlight on the role of kinesin superfamily protein 2A (KIF2A).

Microtubules play a central role in cytoskeletal changes during neuronal development and maintenance. Microtubule dynamics is essential to polarity and shape transitions underlying neural cell division, differentiation, motility, and maturation. Kinesin superfamily protein 2A is a member of human kinesin 13 gene family of proteins that depolymerize and destabilize microtubules.

KIF2A deficiency causes early-onset neurodegeneration.

KIF2A is an atypical kinesin that has the capacity to depolymerize microtubules. Patients carrying mutations in KIF2A suffer from progressive microcephaly and mental disabilities. While the role of this protein is well documented in neuronal migration, the relationship between its dysfunction and the pathobiology of brain disorders is unclear.

The Celsr3-Kif2a axis directs neuronal migration in the postnatal brain.

The tangential migration of immature neurons in the postnatal brain involves consecutive migration cycles and depends on constant remodeling of the cell cytoskeleton, particularly in the leading process (LP). Despite the identification of several proteins with permissive and empowering functions, the mechanisms that specify the direction of migration remain largely unknown. Here, we report that planar cell polarity protein Celsr3 orients neuroblasts migration from the subventricular zone (SVZ) to olfactory bulb (OB).

Linking Cell Polarity to Cortical Development and Malformations.

Cell polarity refers to the asymmetric distribution of signaling molecules, cellular organelles, and cytoskeleton in a cell. Neural progenitors and neurons are highly polarized cells in which the cell membrane and cytoplasmic components are compartmentalized into distinct functional domains in response to internal and external cues that coordinate polarity and behavior during development and disease. In neural progenitor cells, polarity has a prominent impact on cell shape and coordinate several processes such as adhesion, division, and fate determination.

Defects in neural guidepost structures and failure to remove leptomeningeal cells from the septal midline behind the interhemispheric fusion defects in Netrin1 deficient mice.

Corpus callosum (CC) is the largest commissural tract in mammalian brain and it acts to coordinate information between the two cerebral hemispheres. During brain development CC forms at the boundary area between the cortex and the septum and special transient neural and glial guidepost structures in this area are thought to be critical for CC formation. In addition, it is thought that the fusion of the two hemispheres in the septum area is a prerequisite for CC formation.

Pinkbar is an epithelial-specific BAR domain protein that generates planar membrane structures.

Bin/amphipysin/Rvs (BAR)-domain proteins sculpt cellular membranes and have key roles in processes such as endocytosis, cell motility and morphogenesis. BAR domains are divided into three subfamilies: BAR- and F-BAR-domain proteins generate positive membrane curvature and stabilize cellular invaginations, whereas I-BAR-domain proteins induce negative curvature and stabilize protrusions. We show that a previously uncharacterized member of the I-BAR subfamily, Pinkbar, is specifically expressed in intestinal epithelial cells, where it localizes to Rab13-positive vesicles and to the plasma membrane at intercellular junctions.

Netrin1 is required for neural and glial precursor migrations into the olfactory bulb.

Netrin1 (NTN1) deficiency in mouse brain causes defects in axon guidance and cell migration during embryonic development. Here we show that NTN1 is required for olfactory bulb (OB) development at late embryogenesis and at early postnatal stages to facilitate the accumulation of proper numbers of granular and glomerular neuron subtypes and oligodendrocytes into the OB. In addition to the analysis of Ntn1-/- mice we made tissue and neurosphere cultures to clarify the role of NTN1 in the anterior forebrain.

Missing-in-metastasis MIM/MTSS1 promotes actin assembly at intercellular junctions and is required for integrity of kidney epithelia.

MIM/MTSS1 is a tissue-specific regulator of plasma membrane dynamics, whose altered expression levels have been linked to cancer metastasis. MIM deforms phosphoinositide-rich membranes through its I-BAR domain and interacts with actin monomers through its WH2 domain. Recent work proposed that MIM also potentiates Sonic hedgehog (Shh)-induced gene expression.

Gata2 is required for the development of inner ear semicircular ducts and the surrounding perilymphatic space.

Gata2 has essential roles in the development of many organs. During mouse inner ear morphogenesis, it is expressed in otic vesicle and the surrounding periotic mesenchyme from early on, but no defects in the ear development of Gata2 null mice have been observed before lethality at embryonic day (E) 10.5.

ABBA regulates plasma-membrane and actin dynamics to promote radial glia extension.

Radial glia play key roles in neuronal migration, axon guidance, and neurogenesis during development of the central nervous system. However, the molecular mechanisms regulating growth and morphology of these extended cells are unknown. We show that ABBA, a novel member of the IRSp53-MIM protein family, is enriched in different types of radial glia.