C9orf72 Conditional Knockout mouse models

Faithful ALS and frontotemporal dementia modeling begins at C9orf72 (historically annotated 3110043O21Rik), the mouse ortholog of human C9ORF72, which encodes a DENN-domain guanine nucleotide exchange factor that partners stoichiometrically with SMCR8 and WDR41 to govern RAB GTPase cycling, ULK1-dependent autophagy initiation, and lysosomal trafficking. Disease arises from a GGGGCC hexanucleotide repeat expansion in intron 1 acting through three intertwined routes: transcriptional silencing and haploinsufficiency, sequestration of RNA-binding proteins into sense and antisense foci, and repeat-associated non-AUG translation into dipeptide repeat species including poly(GA), poly(GR), and poly(PR). Allele choice therefore encodes the hypothesis. Germline or conditional nulls interrogate loss of function, which in mice yields myeloid and microglial lysosomal defects plus autoimmunity rather than frank motor neuron death, repeat-expansion knockin or BAC alleles test gain of function, and humanized locus replacement enables antisense oligonucleotide and RNA-targeting campaigns. Match allele class to endpoint, pairing neuronal or myeloid Cre drivers with cell-type-restricted questions.

C9orf72 conditional knockout mice carry a floxed allele so you delete function only where Cre is active. The germline allele stays intact until you cross to a tissue specific Cre. Labs reach for this design when a global knockout is lethal, when they need adult onset loss, or when regional redundancy hides a whole body phenotype.