Functional Fluorescence Microscopy Imaging: Quantitative Scanning-Free Confocal Fluorescence Microscopy for the Characterization of Fast Dynamic Processes in Live Cells

Anal Chem. 2019 Sep 3;91(17):11129-11137. doi: 10.1021/acs.analchem.9b01813. Epub 2019 Aug 14.

Abstract

Functional fluorescence microscopy imaging (fFMI), a time-resolved (21 μs/frame) confocal fluorescence microscopy imaging technique without scanning, is developed for quantitative characterization of fast reaction-transport processes in solution and in live cells. The method is based on massively parallel fluorescence correlation spectroscopy (FCS). Simultaneous excitation of fluorescent molecules in multiple spots in the focal plane is achieved using a diffractive optical element (DOE). Fluorescence from the DOE-generated 1024 illuminated spots is detected in a confocal arrangement by a matching matrix detector comprising 32 × 32 single-photon avalanche photodiodes (SPADs). Software for data acquisition and fast auto- and cross-correlation analysis by parallel signal processing using a graphic processing unit (GPU) allows temporal autocorrelation across all pixels in the image frame in 4 s and cross-correlation between first- and second-order neighbor pixels in 45 s. We present here this quantitative, time-resolved imaging method with single-molecule sensitivity and demonstrate its usefulness for mapping in live cell location-specific differences in the concentration and translational diffusion of molecules in different subcellular compartments. In particular, we show that molecules without a specific biological function, e.g., the enhanced green fluorescent protein (eGFP), exhibit uniform diffusion. In contrast, molecules that perform specialized biological functions and bind specifically to their molecular targets show location-specific differences in their concentration and diffusion, exemplified here for two transcription factor molecules, the glucocorticoid receptor (GR) before and after nuclear translocation and the Sex combs reduced (Scr) transcription factor in the salivary gland of Drosophila ex vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Dexamethasone / pharmacology
  • Drosophila Proteins / genetics*
  • Drosophila Proteins / metabolism
  • Drosophila melanogaster
  • Gene Expression
  • Genes, Reporter
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Humans
  • Microscopy, Confocal / instrumentation
  • Microscopy, Confocal / methods*
  • Microscopy, Fluorescence / instrumentation
  • Microscopy, Fluorescence / methods*
  • Osteoblasts / drug effects
  • Osteoblasts / metabolism
  • Osteoblasts / ultrastructure
  • PC12 Cells
  • Protein Transport / drug effects
  • Quantum Dots
  • Rats
  • Receptors, Opioid, mu / genetics*
  • Receptors, Opioid, mu / metabolism
  • Salivary Glands / metabolism
  • Salivary Glands / ultrastructure
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism

Substances

  • Drosophila Proteins
  • Oprm1 protein, rat
  • Receptors, Opioid, mu
  • Scr protein, Drosophila
  • Transcription Factors
  • enhanced green fluorescent protein
  • Green Fluorescent Proteins
  • Dexamethasone