What makes humans the most advanced organisms on the planet? Arguably, it is the mind-boggling diversity and complexity of the neural circuitry in the cerebral cortex, the most recently evolved vertebrate brain region. Not surprisingly, that very diversity and complexity have made the secrets of the cerebral cortex's marvelous capabilities difficult to dissect. To help dissect them, a research team led by scientists at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, has generated and characterized 18 new Cre and inducible CreER knockin driver mouse lines (Taniguchi et al. 2011). All 18 lines are available at The Jackson Laboratory (see list at the end of this article).
The new Cre-driver lines will be particularly useful for understanding the development and functions of subpopulations of GABAergic interneurons. These multipolar neurons are typically inhibitory and connect to the brain's afferent neurons, which carry nerve impulses from our sense organs to the central nervous system. GABAergic interneurons are so named because they transmit nerve impulses primarily via gamma-aminobutyric acid (GABA), the chief inhibitory neurotransmitter in the mammalian central nervous system.
The 18 new Cre-driver lines target more than a dozen genes in GABAergic subpopulations and lineages: some encode broadly expressed enzyme and transcription factors; others encode narrowly expressed neuropeptides, enzymes and calcium-binding proteins. Because the Cre-encoding cassettes in the new lines target either translation initiation codons or sites immediately downstream of translation STOP codons of endogenous genes, the Cre activity precisely and reliably engages endogenous gene expression. Researchers using the new Cre-driver lines in combination with Flp drivers will be able to target GABAergic interneuron subpopulations with greater specificity than ever before.
To assay recombination patterns, the research team used four reporter alleles, all knocked in to the Rosa26 locus: 1) RCE-LoxP, a loxP-STOP-loxP-GFP reporter, 2) RCE-Frt, an frt-STOP-frt-GFP reporter, 3) Ai9, a loxP-STOP-loxP- tdTomato reporter, and 4) RCE-dual, a loxP-STOP-loxPfrt-STOP-frt-GFP reporter that expresses GFP upon the intersection of Cre and Flp recombination.
Primarily, the Cold Spring Harbor team characterized the new lines' neocortex and hippocampus Cre activity, but they also documented Cre activity throughout the brain, from the retina to the spinal cord. More detailed characterization, including atlases of Cre-dependent reporter expression, is documented in the Cre-driver website.
The new Cre-driver lines will go a long way toward elucidating the origins, organization, differentiation and functions of the cerebral cortex's neuronal circuitry. They will also advance our understanding of the pathogenic mechanisms of neurodevelopmental and psychiatric disorders.
List of the Zjh Cre-driver lines available at JAX
| Strain name (Stock number) |
Cre expression (controlled by the targeted endogenous gene promoters/enhancers) |
|---|---|
|
STOCK Gad2tm2(cre)Zjh/J (010802) |
Expresses Cre in glutamic acid decarboxylase 2- (Gad2)-expressing neurons |
|
STOCK Ssttm2.1(cre)Zjh/J (013044) |
Expresses Cre in somatostatin- (Sst)-expressing neurons |
|
STOCK Viptm1(cre)Zjh/J (010908) |
Expresses Cre in vasoactive intestinal polypeptide- (Vip)-expressing neurons |
|
STOCK Ccktm1.1(cre)Zjh/J (012706) |
Expresses Cre in cholecystokinin- (Cck)-expressing neurons |
|
B6(Cg)-Calb2tm1(cre)Zjh/J (010774) |
Expresses Cre in calretinin (Calb2) neurons in the brain and cortex |
|
B6(Cg)-Crhtm1(cre)Zjh/J (012704) |
Expresses Cre in corticotropin releasing hormone- (Crh)-expressing neurons |
|
STOCK Corttm1(cre)Zjh/J (010910) |
Expresses Cre in cortistatin- (Cort)-expressing neurons |
|
STOCK Gad2tm1(cre/ERT2)Zjh/J (010702) |
Expresses CreERT2 fusion protein (Gad2 function abolished) |
|
B6(Cg)-Ssttm1(cre/ERT2)Zjh/J (010708) |
Expresses CreERT2 fusion protein (somatostatin (Sst) function abolished) |
|
B6(Cg)-Pvalbtm1(cre/ERT2)Zjh/J (010777) |
Expresses CreERT2 fusion protein in parvalbumin- (Pvalb)-positive neurons in neocortex and cerebellum (Pvalb function abolished) |
|
B6(Cg)-Calb2tm2.1(cre/ERT2)Zjh/J (013730) |
Expresses tamoxifen-induced CreERT2 fusion protein in calretinin (Calb2)-positive brain neurons (Calb2 function abolished) |
|
B6(Cg)-Ccktm2.1(cre/ERT2)Zjh/J (012710) |
Expresses tamoxifen-inducible CreERT2 fusion protein in cholecystokinin- (Cck)-positive cortex neurons (Cck function abolished) |
|
B6;129S-Nos1tm1.1(cre/ERT2)Zjh/J (014541) |
Expresses tamoxifen-inducible CreERT2 fusion protein in nitric oxide synthase 1- (nNOS)-positive GABAergic neurons (Nos1 function abolished) |
|
B6;129S-Nkx2-1tm1.1(cre/ERT2)Zjh/J (014552) |
Expresses CreERT2 fusion protein in Nkx2.1-positive neurons and medial ganglionic eminence progenitor cells |
|
B6;129S-Dlx1tm1(cre/ERT2)Zjh/J (014551) |
Expresses CreERT2 fusion protein (distal-less homeobox 1 (Dlx1) function abolished) |
|
B6(Cg)-Dlx5tm1(cre/ERT2)Zjh/J (010705) |
Expresses CreERT2 fusion protein (distal-less homeobox 5 (Dlx5) function abolished) |
|
B6(Cg)-Lhx6tm1(cre/ERT2)Zjh/J (010776) |
Expresses CreERT2 fusion protein in the cortex (LIM homeobox protein 6 (Lhx6) function abolished) |
|
B6(Cg)-Etv1tm1.1(cre/ERT2)Zjh/J (013048) |
Expresses tamoxifen-inducible CreERT2 fusion protein in ets variant gene 1- (Etv1)-positive neurons (Etv1 function abolished) |