Foxn4: A multi-faceted transcriptional regulator of cell fates in vertebrate development

Abstract

Vertebrate development culminates in the generation of proper proportions of a large variety of different cell types and subtypes essential for tissue, organ and system functions in the right place at the right time. Foxn4, a member of the forkhead box/winged-helix transcription factor superfamily, is expressed in mitotic progenitors and/or postmitotic precursors in both neural (e.g., retina and spinal cord) and non-neural tissues (e.g., atrioventricular canal and proximal airway). During development of the central nervous system, Foxn4 is required to specify the amacrine and horizontal cell fates from multipotent retinal progenitors while suppressing the alternative photoreceptor cell fates through activating Dll4-Notch signaling. Moreover, it activates Dll4-Notch signaling to drive commitment of p2 progenitors to the V2b and V2c interneuron fates during spinal cord neurogenesis. In development of non-neural tissues, Foxn4 plays an essential role in the specification of the atrioventricular canal and is indirectly required for patterning the distal airway during lung development. In this review, we highlight current understanding of the structure, expression and developmental functions of Foxn4 with an emphasis on its cell-autonomous and non-cell-autonomous roles in different tissues and animal model systems. Xiang M Q, Li S G. Foxn4: A multi-faceted transcriptional regulator of cell fates in vertebrate development. Sci China Life Sci, 2013, 56: 985 -993,

Temporal expression of CD184(CXCR4) and CD171(L1CAM) identifies distinct early developmental stages of human retinal ganglion cells in embryonic stem cell derived retina

“…Also, RT-qPCR analysis of the CD184hi fraction of sorted cells showed an enrichment for several factors, FOXN4 , PROX1 , NEUROD1 , NEUROD4(MATH3) , in addition to ATOH7 , that are known to be expressed as RPCs acquire competence for generating amacrine, horizontal, and photoreceptor cells, and transition toward cell cycle exit (Akagi et al, 2004; Boije et al, 2013; Dyer et al, 2003; Fujitani et al, 2006; Inoue et al, 2002; S. Li et al, 2004; Mao et al, 2008; 2013; Xiang and S. Li, 2013) (Figure 7C). Together these data raise the possibility that as some RPCs move toward cell cycle exit or neurogenic divisions to generate RGCs, and possibly other cell types, they boost CD184 expression to higher levels.…”

Vsx1 Transiently Defines an Early Intermediate V2 Interneuron Precursor Compartment in the Mouse Developing Spinal Cord

“…The segregation of the V2a and V2b lineages relies on the asymmetrical activation of the Notch pathway by Dll4, which stimulates Notch signaling in surrounding cells and thereby promotes V2b differentiation, restricting V2a differentiation to cells with lower Notch activity (Li et al, 2005; Del Barrio et al, 2007; Peng et al, 2007; Misra et al, 2014; Zou et al, 2015). Proper activation of this pathway requires mosaic expression of several transcriptional regulators including Foxn4 and Ascl1 in the p2 domain (Li et al, 2005; Del Barrio et al, 2007; Xiang and Li, 2013; Misra et al, 2014). To assess whether the production of the Vsx1 + cells also depends on this network, we evaluated the phenotype of these populations in embryos mutant for Foxn4 , Ascl1 or PS1 .…”

Tfap2a and 2b act downstream of Ptf1a to promote amacrine cell differentiation during retinogenesis

“…Interestingly, our previous microarray profiling analysis has identified the same two genes as those significantly downregulated in Foxn4 mutant retinas [ 29 ]. Given the known epistatic relationship between Foxn4 and Ptf1a during retinal development [ 15 , 17 ], however, Tfap2a and 2b are unlikely to be direct targets of Foxn4.…”

“…Conversely, its misexpression in mouse and chick retinas promoted the amacrine and horizontal cell fates [ 13 , 14 ]. Gene expression profiling identified Ptf1a as one of the most downregulated genes in Foxn4 null mutant retinas, and in Ptf1a mutants, there is similar loss of all horizontal cells and the majority of amacrine cells; however, there is no change in Foxn4 expression [ 15 , 16 ], thereby defining a Foxn4-Ptf1a pathway controlling the specification of amacrine and horizontal cells [ 4 , 15 , 17 ]. Indeed, Ptf1a overexpression has been shown to promote amacrine and horizontal cell differentiation in the chick, Xenopus and zebrafish [ 18 - 20 ].…”