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Golgi Releases a Numb Regulator

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Science's STKE  10 Apr 2007:
Vol. 2007, Issue 381, pp. tw123
DOI: 10.1126/stke.3812007tw123

Numb is a signaling protein that functions in two different aspects of neuronal specification: Numb promotes progenitor cell fates over neuronal fates, and it is necessary for neuronal differentiation. Numb is segregated during interphase onto one side of the dividing progenitor cell, where dNumb specifies a particular sensory cell fate in Drosophila or self-renewal of neuronal progenitors in mice [mNumb or Numb-like (Numbl)]. Shortly after mitosis, Numb appears in the cell from which it was originally excluded, where it contributes to the differentiation of that cell: in Drosophila, the formation of the sensory organ hair cell, and in mice, neuronal differentiation. Zhou et al. provide insight into how Numb can serve these two different, mitotically regulated functions. They identified the Golgi protein ACBD3 (for acyl-coenzyme A-binding domain protein 3) as an mNumb-interacting protein in a yeast two-hybrid screen, and the interaction was confirmed by coimmunoprecipitation of transfected cells. Deletion of the ACBD3 binding domain from mNumb rendered it incapable of rescuing sensory organ defects caused by dNumb deficiency when expressed in Drosophila. Knockout of ACBD3 in mouse caused the death of embryos, and detailed analysis of the embryos revealed phenotypes similar to those associated with Numb deficiency, such as loss of progenitor cells leading to thinning of the neuroepithelium. Although ACBD3 and mNumb and Numbl were all present in the wild-type mouse neuroprogenitor cells of the neuroepithelium, their subcellular distributions were different: ACBD3 colocalized with Golgi markers in interphase cells, and the Numb proteins were cytosolic and membrane-associated. ACBD3 became more diffuse and cytosolically distributed during mitosis at a time when Numb proteins had already segregated to the apical side of the neuroprogenitor cell. This redistribution of ACBD3 was critical to neuronal differentiation because replacement of the endogenous mouse ACBD3 gene in neural progenitor cells with a myristoylated form that was uniformly associated with the plasma membrane disrupted neuron formation throughout the nervous system, a phenotype similar to that associated with forcing uniform distribution of Numb. The authors suggest that Golgi fragmentation during mitosis may release ACBD3, allowing it to regulate Numb signaling, which may provide a mechanism to couple cell fate specification with the cell cycle.

Y. Zhou, J. B. Atkins, S. B. Rompani, D. L. Bancescu, P. H. Petersen, H. Tang, K. Zou, S. B. Stewart, W. Zhong, The mammalian Golgi regulates Numb signaling in asymmetric cell division by releasing ACBD3 during mitosis. Cell 129, 163-178 (2007). [Online Journal]

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